Aurora Kinase Modulators and Method of Use

ABSTRACT

The present invention relates to chemical compounds having a general formula I 
     
       
         
         
             
             
         
       
     
     wherein A 1 , A 2 , C 1 , C 2 , D, L 1 , L 2 , Z and R 3 , R 4 , R 6 , R 7  and R 8  are defined herein, which are capable of modulating Aurora kinase protein activity, thereby influencing various disease states and conditions related to the activities of Aurora kinase proteins. For example, the compounds are capable of influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, processes of preparing compounds of the invention, synthetic intermediates and methods of treatment of conditions related to the activity of Aurora kinase.

This application is a continuation patent application, and claims thebenefit, of U.S. non-provisional patent application Ser. No. 11/655,642filed Jan. 18, 2007, which in turn claims the benefit of U.S.Provisional Application No. 60/761,675, filed Jan. 23, 2006, both ofwhich are hereby incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The invention relates to the field of pharmaceutical agents and, morespecifically, is directed to compounds and compositions useful formodulating Aurora kinase, and to uses and methods for managing cellproliferation and for treating cancer.

BACKGROUND OF THE INVENTION

Cancer is one of the most widespread diseases afflicting mankind and amajor cause of death worldwide. In an effort to find an effectivetreatment or a cure for one or more of the many different types ofcancer, over the last couple of decades, numerous groups have invested atremendous amount of time, effort and financial resources. However, todate, of the available cancer treatments and therapies, only a few offerany considerable degree of success.

Cancer is often characterized by unregulated cell proliferation. Damageto one or more genes, responsible for the cellular pathways, whichcontrol progress of proliferation through the cell cycle, typicallycauses the loss of normal regulation of cell proliferation. These genescode for various proteins, which participate in a cascade of events,including protein phosphorylation, leading to cell-cycling progressionand cell proliferation. Various kinase proteins have been identified,which play roles in the cell cycling cascade and in proteinphosphorylation in particular.

One class of proteins found to play a part in cell cycling and,therefore, cell proliferation is the Aurora kinase family of proteins.Aurora kinases are enzymes of the serine/threonine kinase family ofproteins, which play an important role in protein phosphorylation duringthe mitotic phase of the cell cycle. There are three known members ofthe Aurora kinase family, Aurora A, Aurora B and Aurora C, also commonlyreferred to as Aurora 2, Aurora 1, and Aurora 3, respectively.

The specific function of each Aurora kinase member in mammalian cellcycle has been studied. Aurora-A is localized to the centrosome duringinterphase and is important for centrosome maturation and to maintainseparation during spindle assembly. Aurora-B localizes to thekinetochore in the G2 phase of the cell cycle until metaphase, andrelocates to the midbody after anaphase. Aurora-C was thought tofunction only in meiosis, but more recently has been found to be moreclosely related to Aurora-B, showing some overlapping functions andsimilar localization patterns in mitosis. Each aurora kinase appears toshare a common structure, including a highly conserved catalytic domainand a very short N-terminal domain that varies in size. (See R. Giet andC. Prigent, J. Cell. Sci., 112:3591-3601 (1999)).

Aurora kinases appear to be viable targets for the treatment of cancer.Aurora kinases are overexpressed in various types of cancers, includingcolon, breast, lung, pancrease, prostate, bladder, head, neck, cervix,and ovarion cancers. The Aurora-A gene is part of an amplicon found in asubset of breast, colon, ovarian, liver, gastric and pancreatic tumors.Aurora-B has also been found to be overexpressed in most major tumortypes. Overexpression of Aurora-B in rodent fibroblasts inducestransformation, suggesting that Aurora-B is oncogenic. More recently,Aurora-B mRNA expression has been linked to chromosomal instability inhuman breast cancer. (Y. Miyoshi et al., Int. J. Cancer, 92:370-373(2001)).

Further, inhibition of one or more of the Aurora kinases by severalparties has been shown to inhibit cell proliferation and triggerapoptosis in several tumor cell lines. Particularly, inhibition ofAurora has been found to arrest cell cycling and promote programmed celldeath via apoptosis. Accordingly, there has been a strong interest infinding inhibitors of Aurora kinase proteins.

Thus, the inhibition of Aurora kinases has been regarded as a promisingapproach for the development of novel anti-cancer agents. For example,WO 04/039774 describes aza-quinazolinones for treating cancer viainhibiton of Aurora kinase, WO 04/037814 describes indazolinones fortreating cancer via inhibiton of Aurora-2 kinase, WO 04/016612 describes2, 6, 9-substituted purine derivatives for treating cancer via inhibitonof Aurora kinase, WO 04/000833 describes tri- and tetra-substitutedpyrimidine compounds useful for treating Aurora-mediated diseases, WO04/092607 describes crystals useful for screening, designing andevaluating compounds as agonists or antagonists of Aurora kinase andU.S. Pat. No. 6,919,338 and WO 03/055491 each describe substitutedquinazoline derivatives as inhibitors of Aurora-2 kinase.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a new class of compounds useful formodulating one or more of the Aurora kinase enzymes and for treatingAurora kinase-mediated conditions and/or diseases, including cancer. Inone embodiment of the invention, the compounds, includingpharmaceutically acceptable salts thereof, are generally defined byFormula I

wherein A¹, A², C¹, C², D, L¹, L², Z and R³⁻⁸ are defined herein.

In another embodiment, the invention provides compounds of Formulas IIand III, which are similar in structure to Formula I above.

The invention also provides processes for making compounds of FormulasI-III, as well as intermediates useful in such processes.

The compounds provided by the invention have kinase modulatory activityand, in particular, inhibitory activity, including, without limitation,Aurora kinase inhibitory activity.

To this end, the invention further provides the use of these compounds,as well as their pharmaceutically acceptable salts, in the preparationand manufacture of a medicament for therapeutic, prophylactic, acute orchronic treatment of cancer. Thus, these compounds are useful in themanufacture of anti-cancer medicaments. More particularly, thesecompounds are useful in the manufacture of a medicament to attenuate orprevent disorders through inhibition of Aurora kinase activity. Forexample, in one embodiment, the invention provides a pharmaceuticalcomposition (also referred to herein as a medicament) comprising atherapeutically-effective amount of a compound of Formula I, II or IIIin association with at least one pharmaceutically-acceptable carrier,adjuvant or diluent.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the invention, compounds useful for treating Aurorakinase and related disorders, including cancer and inflammation, aredefined by Formula I:

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt,derivative or prodrug thereof, wherein each of A¹ and A², independently,is N or CR⁹, provided that at least one of A¹ and A² is N;

C¹ is N or CR¹⁹;

C² is N or CH;

D is

-   -   wherein D¹ is N or CR¹¹;    -   D² is N or CR¹²;    -   D³ is N or CR²;    -   D⁴ is NR^(1a), O, S or CR¹²;    -   D⁵ is N or CR²;    -   R¹ is H, OR¹⁴, SR¹⁴, OR¹⁵, SR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,        (CHR¹⁵)_(n)R¹⁴, (CHR¹⁵)_(n)R¹⁵ or R¹⁵;    -   R^(1a) is H, CN or C₁₋₁₀alkyl;    -   alternatively R¹ taken together with either of R¹¹ and R^(1a)        and the carbon or nitrogen atoms to which they are attached form        a partially or fully unsaturated 5- or 6-membered ring of carbon        atoms optionally including 1-3 heteroatoms selected from O, N        and S, and the ring optionally substituted independently with        1-3 substituents of oxo, R¹⁵, SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, OC(O)R¹⁵,        COOR¹⁵, C(O)R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁴R¹⁵ or NR¹⁵R¹⁵; and    -   R² is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴,        C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,        C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,        NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵,        S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵,        NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵        or R¹⁵;

L¹ is NR³, O, S, C(O), S(O), SO₂ or CR³R³;

L² is NR³, O, S, C(O), S(O), SO₂ or CR³R³;

Z is a fully unsaturated 5-6 membered first monocyclic ring, said firstring (1) formed of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, (2) optionally fused to a partially or fullysaturated or fully unsaturated 5-6 membered second monocyclic ringformed of carbon atoms optionally including 1-3 heteroatoms selectedfrom O, N, or S, and (3) wherein 0, 1, 2 or 3 atoms of each of saidfirst and second ring is optionally substituted independently with 1-3substituents of R⁵;

each of R³ and R⁴, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵,NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(0)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵;

alternatively, either of R³ or R⁴, independently, taken together withR¹⁰ and the carbon atoms to which they are attached form a partially orfully unsaturated 5- or 6-membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-3 substituents of R¹³, R¹⁴or R¹⁵;

each R⁵ is, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴,S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵;

each of R⁶, R⁷ and R⁸, independently, is R¹³, R¹⁴ or R¹⁵;

alternatively, either of R⁶ or R⁸, independently, taken together with R⁷and the carbon atoms to which they are attached form a fully saturatedor partially or fully unsaturated 5- or 6-membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, and thering optionally substituted independently with 1-4 substituents of R¹³,R¹⁴ or R¹⁵;

each of R⁹, R¹⁰, R¹¹ and R¹², independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵,NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵,C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴,S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵;

R¹³ is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵,OC(O)R¹⁴, OC(O)R¹⁵, COOR¹⁴, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, C(O)C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), NR¹⁵C(O)C(O)NR¹⁴R¹⁵,NR¹⁵C(O)C(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵,NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR²⁵R¹⁵ or NR¹⁵S(O)₂NR¹⁵R¹⁵;

R¹⁴ is a partially or fully saturated or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, the ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, the heteroatoms selected from O, N, or S,wherein 0, 1, 2 or 3 atoms of each ring is optionally substitutedindependently with 1-5 substituents of R¹⁵;

R¹⁵ is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂,acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; and

n is 0, 1, 2, 3 or 4;

provided that (1) no more than one of D¹ and D² is N, and (2) each of L¹and L² is, independently, bound to the first ring of Z.

Accordingly, the above embodiment of the present invention includedpyridine and pyrimidine D ring compounds while not encompassing triazineD-ring compounds (wherein both D¹ and D² are N, respectively). TriazineD-ring compounds (Formula III) are described in another embodimentherein below. In addition, the above embodiment includes compoundswherein both of L¹ and L² linkers are attached to the first Z ring, andnot one of L¹ and L² substituted on the first ring while the other of L¹and L² is substituted on a second ring of Z (where Z is a fused ringsystem for example).

In another embodiment, Formula I includes compounds wherein each of A¹and A², independently, is N or CR⁹, provided that at least one of A¹ andA² is N, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein A¹ is N, inconjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein A¹ is CR⁹,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein A² is N, inconjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein each of A¹and A², independently, is N, in conjunction with any of the above orbelow embodiments.

In another embodiment, Formula I includes compounds wherein A² is CR⁹,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein D is

in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein D is

in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein D¹ is N andD² is CR¹², in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein D² is N andD¹ is CR¹¹, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein D¹ is CR¹¹and D² is CR¹², in conjunction with any of the above or belowembodiments.

In another embodiment, Formula I includes compounds wherein D is

wherein D¹ is N, D² is CR¹² and D³ is CH, in conjunction with any of theabove or below embodiments.

In another embodiment, Formula I includes compounds wherein D is

wherein D¹ is CR¹¹, D² is N and D³ is CH, in conjunction with any of theabove or below embodiments.

In another embodiment, Formula I includes compounds wherein C¹ is N orCR¹⁰, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein C¹ is CR¹⁰,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein C² is N orCH, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein C² is N, inconjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein C¹ is CR¹⁰,C² is N and R² is H, halo, NO₂, CN, C₁₋₁₀alkyl or C₁₋₁₀alkoxyl, inconjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein C¹ is CR¹⁰and R¹⁰ is H, halo, haloalkyl, haloalkoxyl, CN, OH, SH, NO₂, NH₂,acetyl, C₁₋₁₀-alkyl or C₁₋₁₀-alkoxyl,

C² is N and R² is H, halo, NO₂, CN, C₁₋₁₀alkyl or C₁₋₁₀alkoxyl, inconjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L¹ is NR³,O, S, C(O), S(O), SO₂ or CR³R³, in conjunction with any of the above orbelow embodiments.

In another embodiment, Formula I includes compounds wherein L¹ is O orS, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L¹ is NR³,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L¹ is NR¹⁵,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L¹ is NH, inconjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L¹ is C(O),S(O) or SO₂, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L¹ is CR³R³,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L² is NR³,O, S, C(O), S(O), SO₂ or CR³R³, in conjunction with any of the above orbelow embodiments.

In another embodiment, Formula I includes compounds wherein L² is O orS, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L² is NR³,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L² is NR¹⁵,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L² is NH, inconjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L² is C(O),S(O) or SO₂, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L² is CR³R³,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L¹ is NR¹³,O, CHR¹³, S, C(O), S(O) or SO₂ and R² is H, halo, NO₂, CN, C₁₋₁₀alkyl orC₁₋₁₀alkoxyl, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein the firstmonocyclic ring of Z is phenyl, pyridyl, pyrimidinyl, pyridazinyl,pyazinyl, triazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl,isoxazolyl, or isothiazolyl, in conjunction with any of the above orbelow embodiments.

In another embodiment, Formula I includes compounds wherein the firstmonocyclic ring of Z is a fully unsaturated 6-membered ring, and L¹ andL² are para oriented to one another on the first monocyclic ring of Z,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein L² is NR¹⁵,O or S; each of R³, R⁴ and R⁹, independently, is H; C¹ is CR¹⁰; and

Z is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,thiophenyl, furyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl,triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl,isoxazolyl or isothiazolyl, wherein L¹ and L², together, arepara-oriented to one another on ring Z, wherein ring Z is optionallysubstituted with 1-5 substitutions of R¹⁵, in conjunction with any ofthe above or below embodiments.

In another embodiment, Formula I includes compounds wherein each of L¹and L², independently, is CHR¹⁵, NR¹⁵, O, S, or C(O), R² is H, halo,NO₂, CN, C₁₋₁₀alkyl or C₁₋₁₀alkoxyl,

each of R³, R⁴ and R⁹, independently, is H, and C¹ is CR¹⁰, inconjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R¹ is H,OR¹⁴, SR¹⁴, OR¹⁵, SR¹⁵, NR¹⁴R¹⁵, (CHR¹⁵)_(n)R¹⁴, (CHR¹⁵)_(n)R¹⁵ or R¹⁵,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R¹ is H, inconjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R¹ is OR¹⁴,SR¹⁴, OR¹⁵ or SR¹⁵, in conjunction with any of the above or belowembodiments.

In another embodiment, Formula I includes compounds wherein R¹ isNR¹⁴R¹⁵ or NR¹⁵R¹⁵, in conjunction with any of the above or belowembodiments.

In another embodiment, Formula I includes compounds wherein R¹ is R¹⁵,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R¹ isC₁₋₁₀alkyl, C₁₋₁₀alkoxyl, C₁₋₁₀alkyl-amino-, aryl-amino-, aryl,heteroaryl, heterocyclyl, heteroaryl-amino-, aryl-alkyl-amino-,heterocyclyl-alkyl-amino- or heteroaryl-alkyl-amino-, in conjunctionwith any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R¹ and R¹¹taken together with the carbon atoms to which they are attached form apartially or fully unsaturated 5- or 6-membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N and S, and thering optionally substituted independently with 1-3 substituents of R¹⁵,SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁴R¹⁵or NR¹⁵R¹⁵, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R² is SR¹⁴,OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵,C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵,NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵),OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵,NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵ or R¹⁵,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R² is H, inconjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R² is OR¹⁴,SR¹⁴, OR¹⁵, SR¹⁵, C(O)R¹⁴ or C(O)R¹⁵, in conjunction with any of theabove or below embodiments.

In another embodiment, Formula I includes compounds wherein R² isNR¹⁴R¹⁵ or NR¹⁵R¹⁵, in conjunction with any of the above or belowembodiments.

In another embodiment, Formula I includes compounds wherein R² isC₁₋₁₀alkyl, C₁₋₁₀alkoxyl, C₁₋₁₀alkyl-amino-, aryl-amino-, aryl,heteroaryl, heterocyclyl, heteroaryl-amino-, aryl-alkyl-amino-,heterocyclyl-alkyl-amino- or heteroaryl-alkyl-amino-, in conjunctionwith any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein each of R³and R⁴, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein each of R³and R⁴, independently, is H, in conjunction with any of the above orbelow embodiments.

In another embodiment, Formula I includes compounds wherein each of R³and R⁴, independently, is R¹⁵, in conjunction with any of the above orbelow embodiments.

In another embodiment, Formula I includes compounds wherein each of R³and R⁴, independently, is C₁₋₁₀alkyl, C₁₋₁₀alkoxyl, C₁₋₁₀alkyl-amino-,aryl-amino-, aryl, heteroaryl, heterocyclyl, heteroaryl-amino-,aryl-alkyl-amino-, heterocyclyl-alkyl-amino- or heteroaryl-alkyl-amino-,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein either of R³or R⁴, independently, taken together with R¹⁰ and the carbon atoms towhich they are attached form a partially or fully unsaturated 5- or6-membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and the ring optionally substitutedindependently with 1-3 substituents of R¹³, R¹⁴ or R¹⁵, in conjunctionwith any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein each R⁵,independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴,C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein each R⁵,independently, is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂,NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, in conjunctionwith any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein each R⁵,independently, is H, halo, haloalkyl, CN, OH, SH, NO₂, NH₂, acetyl,C₁₋₁₀-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, in conjunction with any of the aboveor below embodiments.

In another embodiment, Formula I includes compounds wherein each R⁵,independently, is H, Cl, Br, F, I, CF₃, CF₂CF₃, NO₂, CN, acetyl, oxo,haloalkyl, haloalkoxyl, CN, OH, SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkylamino-,benzyl or phenyl, in conjunction with any of the above or belowembodiments.

In another embodiment, Formula I includes compounds wherein R⁶ is R¹³,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R⁶ is R¹⁴,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R⁶ isphenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyazinyl,triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl,phthalazinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl,benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl,isoxazolyl, isothiazolyl, indolyl, azaindolyl, 2,3-dihydroindolyl,isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,imidazo-pyridinyl, purinyl, benzotriazolyl, oxazolinyl, isoxazolinyl,thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl, dioxozinyl, 2,3-dihydro-1,4-benzoxazinyl,1,3-benzodioxolyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl,cyclohexyl, cycloheptyl or pyranyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹⁵, in conjunctionwith any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R⁶ is R¹⁵,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R⁷ is R¹³,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R⁷ is R¹⁴,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R⁷ is R¹⁵,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R⁷ is H,halo, haloalkyl, haloalkoxyl, CN, OH, NO₂, NH₂, SH, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl orC₁₋₁₀-thioalkoxyl, in conjunction with any of the above or belowembodiments.

In another embodiment, Formula I includes compounds wherein R⁷ is H,halo, haloalkyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino- orC₁₋₁₀-alkoxyl, in conjunction with any of the above or belowembodiments.

In another embodiment, Formula I includes compounds wherein R⁸ is R¹³,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R⁸ is R¹⁴,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R⁸ is R¹⁵,in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R⁸ is H,halo, haloalkyl, haloalkoxyl, CN, OH, NO₂, NH₂, SH, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl orC₁₋₁₀-thioalkoxyl, in conjunction with any of the above or belowembodiments.

In another embodiment, Formula I includes compounds wherein R⁸ is H,halo, haloalkyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino- orC₁₋₁₀-alkoxyl, in conjunction with any of the above or belowembodiments.

In another embodiment, Formula I includes compounds wherein either of R⁶or R⁸, independently, taken together with R⁷ and the carbon atoms towhich they are attached form a fully saturated or partially or fullyunsaturated 5- or 6-membered ring of carbon atoms optionally including1-4 heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-3 substituents of R¹³, R¹⁴ or R¹⁵, inconjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein R⁷ and R⁸taken together with the carbon atoms to which they are attached form afully saturated or partially or fully unsaturated 5- or 6-membered ringof carbon atoms optionally including 1-3 heteroatoms selected from O, N,or S, and the ring optionally substituted independently with 1-4substituents of R¹³, R¹⁴ or R¹⁵, in conjunction with any of the above orbelow embodiments.

In another embodiment, Formula I includes compounds wherein R⁷ and R⁸taken together with the carbon atoms to which they are attached form aphenyl, pyridine or pyrimidine ring, the ring optionally substitutedindependently with 1-4 substituents of R¹³, R¹⁴ or R¹⁵, in conjunctionwith any of the above or below embodiments.

In a further embodiment, the immediately preceeding embodiment includescompounds of Formula I wherein each of A¹ and A², independently, is Nand R⁶ is phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyazinyl,triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl,phthalazinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl,thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl,benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl, cycloheptyl or pyranyl,each of which is optionally substituted independently with 1-5substituents of R¹⁵.

In another embodiment, Formula I includes compounds wherein each of R⁹,R¹⁹, R¹¹ and R¹², independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵,NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵, in conjunction with any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein each of R⁹,R¹⁹, R¹¹ and R¹², independently, is H, halo, haloalkyl, CN, OH, SH, NO₂,NH₂, acetyl, C₁₋₁₀-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, in conjunctionwith any of the above or below embodiments.

In another embodiment, Formula I includes compounds wherein each of R⁹,R¹⁹, R¹¹ and R¹², independently, is H, in conjunction with any of theabove or below embodiments.

In another embodiment, Formula I includes compounds wherein as R¹⁴ isphenyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl, dihydroquinolinyl,tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, tetrahydrofuranyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl,benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl, cycloheptyl, pyranyl ornaphthyl, each of which is optionally independently substituted with 1-3substituents of R¹⁵, in conjunction with any of the above or belowembodiments.

In yet another embodiment, the invention provides compounds generallydefined by Formula II:

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt,derivative or prodrug thereof, wherein

each of A¹ and A², independently, is N or CR⁹, provided that at leastone of A¹ and A² is N;

each of B¹, B², B³ and B⁴, independently, is N or CR⁵, provided that nomore than two of B¹, B², B³ and B⁴ is N;

C¹ is N or CR¹⁰;

D¹ is N or CR¹¹;

D² is N or CR¹²;

L¹ is NR³, O, S or CR³R³;

L² is NR³, O, S or CR³R³;

R¹ is OR¹⁴, SR¹⁴, OR¹⁵, SR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,

(CHR¹⁵)_(n)R¹⁴, (CHR¹⁵)_(n)R¹⁵ or R¹⁵; alternatively R¹ and R¹¹ takentogether with the carbon atoms to which they are attached form apartially or fully unsaturated 5- or 6-membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N and S, and thering optionally substituted independently with 1-3 substituents of oxo,R¹⁵, SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴R¹⁵ or NR¹⁵R¹⁵;

R² is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵,COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴,NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵,NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵,S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵ or R¹⁵;

each of R³ and R⁴, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵,NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵ or R¹⁵;

alternatively, either of R³ or R⁴, independently, taken together withR¹⁰ and the carbon atoms to which they are attached form a partially orfully unsaturated 5- or 6-membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-3 substituents of R¹³, R¹⁴or R¹⁵;

each R⁵ is, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵;

R⁶ is R¹³ or R¹⁴;

each of R⁷ and R⁸, independently, is R¹³, R¹⁴ or R¹⁵;

alternatively, either of R⁷ and R⁸ taken together with the carbon atomsto which they are attached form a fully saturated or partially or fullyunsaturated 5- or 6-membered ring of carbon atoms optionally including1-4 heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-3 substituents of R¹³, R¹⁴ or R¹⁵;

each of R⁹, R¹⁰, R¹¹ and R¹², independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵,NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵ or R¹⁵;

R¹³ is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵,OC(O)R¹⁴, OC(O)R¹⁵, COOR¹⁴, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, C(O)C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), NR¹⁵C(O)C(O)NR¹⁴R¹⁵,NR¹⁵C(O)C(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵,NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵ or NR¹⁵S(O)₂NR¹⁵R¹⁵;

R¹⁴ is a partially or fully saturated or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, the ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, the heteroatoms selected from O, N, or S,wherein 0, 1, 2 or 3 atoms of each ring is optionally substitutedindependently with 1-5 substituents of R¹⁵;

R¹⁵ is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂,acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; and

n is 0, 1, 2, 3 or 4;

provided that no more than one of D¹ and D² is N.

In another embodiment, Formula II includes compounds wherein each of A¹and A², independently, is N;

each of B¹, B², B³ and B⁴, independently, is N or CR⁵, provided that nomore than one of B¹, B², B³ and B⁴ is N;

C¹ is CR¹⁰;

D¹ is N or CR¹¹;

D² is N or CR¹²;

L¹ is NH, O or S;

L² is NH, O or S;

R¹ is H, halo, haloalkyl, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, NHR¹⁴, NHR¹⁵, OR¹⁵, SR¹⁵ or CH₂R¹⁵;

R² is H, halo, NO₂, CN, C₁₋₁₀alkyl or C₁₋₁₀alkoxyl;

each of R³ and R⁴, independently, is SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,C(O)R¹⁴, C(O)R¹⁵ or R¹⁵;

each R⁵ is, independently, is SR¹⁵, OR¹⁵, NR¹⁵R¹⁵, C(O)R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁵), S(O)₂R¹⁵, S(O)₂NR¹⁵R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵ or R¹⁵;

R⁶ is R¹⁴;

each of R⁷ and R⁸, independently, is R¹⁵;

alternatively, either of R⁷ and R⁸ taken together with the carbon atomsto which they are attached form a fully saturated or partially or fullyunsaturated 5- or 6-membered ring of carbon atoms optionally including1-3 heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-4 substituents of R¹³ or R¹⁵; and

each of R⁹, R¹⁰, R¹¹ and R¹², independently, is R¹⁵.

In another embodiment, Formula II includes compounds wherein R¹ isNR¹⁴R¹⁵, NR¹⁵R¹⁵, (CHR¹⁵)_(n)R¹⁴, (CHR¹⁵)_(n)R¹⁵ or R¹⁵; alternativelyR¹ and R¹¹ taken together with the carbon atoms to which they areattached form a partially or fully unsaturated 5- or 6-membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N andS, and the ring optionally substituted independently with 1-3substituents of R¹⁵;

R² is H, halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl,tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine,propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl orphenyl;

each of R³ and R⁴, independently, is H, halo, haloalkyl, CN, NO₂, NH₂,OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine,ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl;

each R⁵ is, independently, is H, halo, haloalkyl, CN, NO₂, NH₂, OH,methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine,ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine ordiisopropylamine;

R⁶ is R¹³ or R¹⁴;

each of R⁷ and R⁸, independently, is R¹⁵;

alternatively, either of R⁷ and R⁸ taken together with the carbon atomsto which they are attached form a fully saturated or partially or fullyunsaturated 5- or 6-membered ring of carbon atoms optionally including1-3 heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-4 substituents of R¹³, R¹⁴ or R¹⁵; and

each of R⁹, R¹⁰, R¹¹ and R¹², independently, is H, halo, haloalkyl, CN,NO₂, NH₂, OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamine,dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine,dipropylamine or diisopropylamine.

In another embodiment, Formula II includes compounds wherein each of A¹and A², independently, is N; and

R⁷ and R⁸ taken together with the carbon atoms to which they areattached form a fully unsaturated 5- or 6-membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, and thering optionally substituted independently with 1-3 substituents of R¹³,R¹⁴ or R¹⁵, in conjunction with any of the above or below embodiments.

In another embodiment, Formula II includes compounds wherein R⁶ isphenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyazinyl,triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl,phthalazinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl,thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl,benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl, cycloheptyl or pyranyl,each of which is optionally substituted independently with 1-5substituents of R¹⁵, in conjunction with any of the above or belowembodiments.

In another embodiment, Formula II includes compounds wherein C¹ is CH;

D¹ is N;

D² is CR¹² wherein R¹² is H, halo, NO₂, CN, C₁₋₁₀alkyl or C₁₋₁₀alkoxyl;

L¹ is NH, O or S;

L² is NH;

R¹ is H, halo, haloalkyl, acetyl, C₁₋₁₀-alkyl or NHR¹⁵;

each of R², R³ and R⁴, independently, is H, halo, C₁₋₁₀alkyl orC₁₋₁₀alkoxyl;

R⁶ is R¹⁴; and

R⁷ and R⁸ taken together with the carbon atoms to which they areattached form a partially or fully unsaturated 5- or 6-membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and the ring optionally substituted independently with 1-4substituents of R¹³ or R¹⁵, in conjunction with any of the above orbelow embodiments.

The embodiments for various of the elements described herein above withrespect to compounds of Formula I also apply to compounds of Formula II,where appropriate, as will be appreciated by those skilled in the art.

In another embodiment, the invention provides compounds generallydefined by Formula III

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt,derivative or prodrug thereof, wherein

each of A¹ and A², independently, is N or CR⁹, provided that at leastone of A¹ and A² is N;

each of B¹, B², B³ and B⁴, independently, is N or CR⁵, provided that nomore than two of B¹, B², B³ and B⁴ is N;

C¹ is N or CR¹⁰;

L¹ is O, S, C(O), S(O), SO₂ or CR³R³;

L² is NR³, O, S or CR³R³;

R¹ is OR¹⁴, SR¹⁴, OR¹⁵, SR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, (CHR¹⁵)_(n)R¹⁴,(CHR¹⁵)_(n)R¹⁵ or R¹⁵; alternatively R¹ and R¹¹ taken together with thecarbon atoms to which they are attached form a partially or fullyunsaturated 5- or 6-membered ring of carbon atoms optionally including1-3 heteroatoms selected from O, N and S, and the ring optionallysubstituted independently with 1-3 substituents of R¹⁵, SR¹⁴, OR¹⁴,SR¹⁵, OR¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁴R¹⁵ or NR¹⁵R¹⁵;

R² is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵,COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴,NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵,NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵,S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵ or R¹⁵;

each of R³ and R⁴, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵,NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵ or R¹⁵;

alternatively, either of R³ or R⁴, independently, taken together withR¹⁰ and the carbon atoms to which they are attached form a partially orfully unsaturated 5- or 6-membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-3 substituents of R¹³, R¹⁴or R¹⁵;

each R⁵ is, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵;

R⁶ is R¹³ or R¹⁴;

each of R⁷ and R⁸, independently, is R¹³, R¹⁴ or R¹⁵;

alternatively, either of R⁷ and R⁸ taken together with the carbon atomsto which they are attached form a fully saturated or partially or fullyunsaturated 5- or 6-membered ring of carbon atoms optionally including1-3 heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-4 substituents of R¹³, R¹⁴ or R¹⁵;

each of R⁹, R¹⁰, R¹¹ and R¹², independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵,NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵ or R¹⁵;

R¹³ is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵,OC(O)R¹⁴, OC(O)R¹⁵, COOR¹⁴, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, C(O)C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), NR¹⁵C(O)C(O)NR¹⁴R¹⁵,NR¹⁵C(O)C(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵,NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵ or NR¹⁵S(O)₂NR¹⁵R¹⁵;

R¹⁴ is a partially or fully saturated or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, the ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, the heteroatoms selected from O, N, or S,wherein 0, 1, 2 or 3 atoms of each ring is optionally substitutedindependently with 1-5 substituents of R¹⁵;

R¹⁵ is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂,acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; and

n is 0, 1, 2, 3 or 4.

The embodiments for various of the elements described herein above withrespect to compounds of Formula I also apply to compounds of FormulaIII, where appropriate, as will be appreciated by those skilled in theart.

In yet another embodiment, Formulas I, II and III include the exemplarycompounds and derivatives, progrugs, solvates, tautomers andpharmaceutically acceptable salt forms thereof, intermediates relatedthereto, which are described in the Examples herein.

DEFINITIONS

The following definitions should further assist in understanding thescope of the invention described herein.

The terms “cancer” and “cancerous” when used herein refer to or describethe physiological condition in mammals that is typically characterizedby unregulated cell growth. Examples of cancer include, withoutlimitation, carcinoma, lymphoma, sarcoma, blastoma and leukemia. Moreparticular examples of such cancers include squamous cell carcinoma,lung cancer, pancreatic cancer, cervical cancer, bladder cancer,hepatoma, breast cancer, colon carcinoma, and head and neck cancer.While the term “cancer” as used herein is not limited to any onespecific form of the disease, it is believed that the methods of theinvention will be particularly effective for cancers which are found tobe accompanied by unregulated levels of Aurora kinase(s) in the mammal.

The terms “treat”, “treating” and “treatment” as used herein refer totherapy, including without limitation, curative therapy, prophylactictherapy, and preventative therapy. Prophylactic treatment generallyconstitutes either preventing the onset of disorders altogether ordelaying the onset of a pre-clinically evident stage of disorders inindividuals.

The term “mammal” as used herein refers to any mammal classified as amammal, including humans, cows, horses, dogs and cats. In one embodimentof the invention, the mammal is a human.

A “pharmaceutically-acceptable derivative” denotes any salt (alsoreferred to as “pharmaceutically-acceptable salt”), any prodrug such asa phospshate or an ester of a compound of this invention, or any othercompound which upon administration to a patient is capable of providing(directly or indirectly) a compound of this invention, or a metaboliteor residue thereof, characterized by the ability to inhibit Aurorakinase.

The phrase “therapeutically-effective” is intended to quantify theamount of each agent, which will achieve the goal of improvement indisorder severity and the frequency of incidence over treatment of eachagent by itself, while avoiding adverse side effects typicallyassociated with alternative therapies.

The terms “ring” and “ring system” refer to a one or more rings,typically fused together where more than one ring, comprising thedelineated number of atoms, said atoms being carbon or, where indicated,a heteroatom such as nitrogen, oxygen or sulfur. The ring itself, aswell as any substitutents thereon, may be attached at any atom thatallows a stable compound to be formed. The term “nonaromatic” ring orring system refers to the fact that at least one, but not necessarilyall, rings in a bicyclic or tricyclic ring system is not fullyunsaturated.

“Leaving groups” generally refer to groups that are displaceable by anucleophile. Such leaving groups are known in the art. Examples ofleaving groups include, but are not limited to, halides (e.g., I, Br, F,Cl), sulfonates (e.g., mesylate, tosylate), sulfides (e.g., SCH₃),N-hydroxsuccinimide, N-hydroxybenzotriazole, and the like. Nucleophilesare species that are capable of attacking a molecule at the point ofattachment of the leaving group causing displacement of the leavinggroup. Nucleophiles are known in the art. Examples of nucleophilicgroups include, but are not limited to, amines, thiols, alcohols,Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions)and the like.

The term “H” denotes a single hydrogen atom. This radical may beattached, for example, to an oxygen atom to form a hydroxyl radical.

Where the term “alkyl” is used, either alone or within other terms suchas “haloalkyl” and “alkylamino”, it embraces linear or branched radicalspreferably having alpha to beta number of carbon atoms. For example aC₁-C₁₀ alkyl is an alkyl comprising 1 to 10 carbon atoms. Examples ofsuch radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like. Itis contemplated herein that alkyl radicals may be optionally substitutedwith various substituents, where indicated.

The term “alkenyl”, alone or in combination, embraces linear or branchedradicals having at least one carbon-carbon double bond and having two ormore carbon atoms. Examples of alkenyl radicals include, withoutlimitation, ethenyl, propenyl, allyl, propenyl, butenyl and4-methylbutenyl. The term “alkenyl” embrace radicals having “cis” and“trans” orientations, or alternatively, “E” and “Z” orientations, asappreciated by those of ordinary skill in the art. It is contemplatedherein that alkenyl radicals may be optionally substituted with varioussubstituents, where indicated.

The term “alkynyl”, alone or in combination, denotes linear or branchedradicals having at least one carbon-carbon triple bond and having two ormore carbon atoms. Examples of alkynyl radicals include, withoutlimitation, ethynyl, propynyl (propargyl), butynyl, and the like. It iscontemplated herein that alkynyl radicals may be optionally substitutedwith various substituents, where indicated.

The term “halo”, alone or in combination, means halogens such asfluorine, chlorine, bromine or iodine atoms.

The term “haloalkyl”, alone or in combination, embraces radicals whereinany one or more of the alkyl carbon atoms is substituted with halo asdefined above. For example, this term includes monohaloalkyl,dihaloalkyl and polyhaloalkyl radicals such as a perhaloalkyl. Amonohaloalkyl radical, for example, may have either an iodo, bromo,chloro or fluoro atom within the radical. Dihalo and polyhaloalkylradicals may have two or more of the same halo atoms or a combination ofdifferent halo radicals. Examples of haloalkyl radicals includefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. “Perfluoroalkyl”, asused herein, refers to alkyl radicals having all hydrogen atoms replacedwith fluoro atoms. Examples include trifluoromethyl andpentafluoroethyl.

The term “hydroxyalkyl”, alone or in combination, embraces linear orbranched alkyl radicals having one or more carbon atoms any one of whichmay be substituted with one or more hydroxyl radicals. Examples of suchradicals include hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxybutyl and hydroxyhexyl.

The term “alkoxy”, alone or in combination, embraces linear or branchedoxy-containing radicals each having alkyl portions of alpha to betanumber of carbon atoms. For example, a C₁₋₁₀ alkoxy radical indicates analkoxide having one to ten carbon atoms, arranged in a linear orbranched fashion, attached to an oxygen atom. Examples of such radicalsinclude methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Alkoxyradicals may be further substituted with one or more halo atoms, such asfluoro, chloro or bromo, to provide “haloalkoxy” radicals. Examples ofsuch radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term “partially or fully saturated” as used herein, refers to amoiety, linear, branched or cyclic in nature, having no atom-atom doubleor triple bonds (fully saturated) or having one or more atom-atom doubleor triple bonds which are arranged such that where the structural moietyis cyclic, the cycle is not fully unsaturated (non-aromatic), asappreciated by those skilled in the art.

The term “fully unsaturated” as used herein, refers to a moiety havingdouble or triple bonds, arranged in a manner such that the structure isaromatic in nature, as appreciated by those skilled in the art.

The term “aryl”, alone or in combination, means a carbocyclic aromaticmoiety containing one, two or even three rings wherein such rings may beattached together in a fused manner. Thus the term “aryl” embracesaromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl,anthracenyl, and indanyl. Said “aryl” group may have 1 or moresubstituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro,cyano, alkoxy and lower alkylamino, and the like. Phenyl substitutedwith —O—CH₂—O— forms an aryl benzodioxolyl substituent. Aryl as usedherein, implies a fully unsaturated ring.

The term “heterocycles” or “heterocyclic radicals”, alone or incombination, embraces saturated, partially saturated and partiallyunsaturated heteroatom-containing ring radicals, where the heteroatomsmay be selected from nitrogen, sulfur and oxygen. This term does notinclude rings containing —O—O—, —O—S— or —S—S— portions. Said“heterocycle” may have 1 or more substituents such as hydroxyl, Boc,halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy,amino and lower alkylamino.

Examples of saturated heterocyclic radicals include saturated 3 to6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated (or partiallyunsaturated) heterocyclyl radicals include dihydrothienyl,dihydropyranyl, dihydrofuryl and dihydrothiazolyl.

The term “heteroaryl” radicals, alone or in combination, embraces fullyunsaturated heteroatom-containing ring radicals, where the heteroatomsmay be selected from nitrogen, sulfur and oxygen. Examples of heteroarylradicals include unsaturated 5 to 6 membered heteromonocyclyl groupcontaining 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl,pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic groupcontaining an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.;unsaturated 5 to 6-membered heteromonocyclic group containing a sulfuratom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl[e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl];unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl].

The terms “heterocycle” and “heteroaryl” also embraces radicals whichare fused/condensed with aryl radicals: unsaturated condensedheterocyclic or heteroaryl groups containing 1 to 5 nitrogen atoms, forexample, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturatedand unsaturated condensed heterocyclic group containing 1 to 2 oxygen orsulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Examples ofheterocyclic radicals include five to ten membered fused or unfusedradicals. Further examples of heteroaryl radicals include quinolyl,isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl,and pyrazinyl. Other examples of heteroaryl radicals are 5- or6-membered heteroaryl, containing one or two heteroatoms selected fromsulfur, nitrogen and oxygen, such as thienyl, furyl, pyrrolyl,indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl radicals.

Examples of non-nitrogen containing heteroaryl include, withoutlimitation, pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl,benzothienyl, and the like.

Examples of partially and fully saturated heterocyclyl include, withoutlimitation, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

The term “sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals —SO₂—.

The term “carbonyl”, whether used alone or with other terms, such as“aminocarbonyl”, denotes —(C═O)—.

The term “alkylthio” embraces radicals containing a linear or branchedalkyl radical, of one to ten carbon atoms, attached to a divalent sulfuratom. An example of “alkylthio” is methylthio, (CH₃S—).

The term “aminoalkyl” and “diaminoalkyl” embraces “N-alkylamino” and“N,N-dialkylamino”, respectively, where amino groups are independentlysubstituted with one alkyl radical and with two alkyl radicals,respectively. Examples of alkylamino radicals include “lower alkylamino”radicals having one or two alkyl radicals of one to six carbon atoms,attached to a nitrogen atom. Suitable alkylamino radicals may be mono ordialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino and the like.

The term “C₁₋₁₀alkyl-amino-” denotes amino groups, which have beensubstituted with one or two alkyl radicals, such as N-methylamino. Thealkylamino radicals may be further substituted on the alkyl portion ofthe radical.

The term “aryl-alkyl-amino-” or “aralkylamino” denotes amino groups,which have been substituted with one or two aryl-substituted-alkylradicals, such as benzyl-amino. The aralkyl-amino radicals may befurther substituted on the aryl or alkyl portion of the radical.

The term “heterocyclyl-alkyl-amino-” denotes amino groups, which havebeen substituted with one or two heterocyclyl-substituted-alkylradicals, such as piperidyl-methyl-amino. The heterocyclyl-alkyl-aminoradicals may be further substituted on the heterocycle or alkyl portionof the radical.

The term “heteroaryl-alkyl-amino-” or “heteroaralkylamino” denotes aminogroups, which have been substituted with one or twoheteroaryl-substituted-alkyl radicals, such as pyrimidyl-amino. Theheteroaralkyl-amino radicals may be further substituted on theheteroaryl or alkyl portion of the radical.

The term “arylamino” denotes amino groups, which have been substitutedwith one or two aryl radicals, such as N-phenylamino. The arylaminoradicals may be further substituted on the aryl ring portion of theradical.

The term “heteroarylamino” denotes amino groups, which have beensubstituted with one or two heteroaryl radicals, such as N-thienylamino.The “heteroarylamino” radicals may be further substituted on theheteroaryl ring portion of the radical.

The term “cycloalkyl” includes saturated carbocyclic groups. Examples ofcycloalkyl groups include C₃-C₆ rings, such as compounds including,cyclopentyl, cyclopropyl, and cyclohexyl.

The term “cycloalkenyl” includes carbocyclic groups having one or morecarbon-carbon double bonds including “cycloalkyldienyl” compounds.Examples of cycloalkenyl groups include C₃-C₆ rings, such as compoundsincluding, without limitation, cyclopentenyl, cyclopentadienyl,cyclohexenyl and cycloheptadienyl.

The term “comprising” is meant to be open ended, including the indicatedcomponent(s) but not excluding other elements.

The terms “Formula I”, “Formula II” and “Formula III” include any subformulas.

The present invention comprises processes for the preparation of acompound of Formulae I and II.

Also included in the family of compounds of Formulas I-III are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formulas I-III may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsinclude, without limitation, hydrochloric, hydrobromic, hydroiodic,nitric, carbonic, sulfuric and phosphoric acid. Examples of organicacids include, without limitation, aliphatic, cycloaliphatic, aromatic,arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organicacids, examples of which are formic, acetic, adipic, butyric, propionic,succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic,β-hydroxybutyric, salicylic, galactaric and galacturonic acid.

Suitable pharmaceutically-acceptable base addition salts of compounds ofFormulas I-III include, without limitation, metallic salts such as saltsmade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc, or salts made from organic bases including primary, secondary,tertiary amines and substituted amines including cyclic amines such ascaffeine, arginine, diethylamine, N-ethyl piperidine, aistidine,glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine,piperazine, piperidine, triethylamine, trimethylamine. All of the saltscontemplated herein may be prepared by conventional means from thecorresponding compound by reacting, for example, the appropriate acid orbase with the compound of Formulas I-III. When a basic group and an acidgroup are present in the same molecule, a compound of Formulas I-III mayalso form internal salts.

General Synthetic Procedures

The compounds of the invention can be synthesized according to thefollowing procedures of Schemes 1-8, wherein the substituents are asdefined for Formulas I-III, above, except where further noted. Thesynthetic methods described below are merely exemplary, and thecompounds of the invention may be synthesized by alternate routes asappreciated by persons of ordinary skill in the art.

The following list of abbreviations used throughout the specificationrepresent the following:

-   ACN, AcCN, MeCN—acetonitrile-   BSA—bovine serum albumin-   Cs₂CO₃—cesium carbonate-   CHCl₃—chloroform-   CH₂Cl₂, DCM—dichloromethane, methylene chloride-   DIBAL—diisobutylaluminum hydride-   DIEA,(iPr₂Net)—diisopropylethylamine-   DME—dimethoxyethane-   DMF—dimethylformamide-   DMAP—4-dimethylaminopyridine-   DMSO—dimethylsulfoxide-   dppa—diphenylphosphoryl azide-   EDC—1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   Et₂O—diethyl ether-   EtOAc ethyl acetate-   FBS—fetal bovine serum-   g, gm—gram-   h, hr—hour-   HBr—hydrobromic acid-   HCl—hydrochloric acid-   HOBt—1-hydroxybenzotriazole hydrate-   H₂—hydrogen-   H₂O₂—hydrogen peroxide-   HATU—O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate-   HPLC—high pressure liquid chromatography-   IPA, IpOH—isopropyl alcohol-   K₂CO₃—potassium carbonate-   MCPBA—meta-chloroperbenzoic acid-   MgSO₄—magnesium sulfate-   MeOH—methanol-   N₂—nitrogen-   NaHCO₃—sodium bicarbonate-   NaOH—sodium hydroxide-   NaH—sodium hydride-   Na₂SO₄—sodium sulfate-   NH₄Cl—ammonium chloride-   NH₄OH—ammonium chloride-   NMP—N-methylpyrrolidinone-   P(t-bu)₃—tri(tert-butyl)phosphine-   PBS—phospate buffered saline-   Pd/C—palladium on carbon-   Pd(PPh₃)₄—palladium(0)triphenylphosphine tetrakis-   Pd(PhCN)₂Cl₂—palladium di-cyanophenyl dichloride-   Pd(OAc)₂—palladium acetate-   Pd₂(dba)₃—bis(dibenzylideneacetone) palladium-   PyBop—benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium    hexafluorophosphate-   RT, rt—room temperature-   RBF—round bottom flask-   rac-BINAP—2,2′-Bis(diphenylphosphine)-1,1′-binaphthyl-   TBTU—O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   TEA, Et₃N—triethylamine-   TFA—trifluoroacetic acid-   THF—tetrahydrofuran

The biaryl ring system (3), including substituted or unsubstitutedpyridyl-pyridines (where ring C and D are both pyridines),pyridyl-pyrimidines (where one of rings C and D is a pyridine and theother is a pyrimidine), pyridyl triazines (where D is a triazine),pyrimidyl-pyrimidines and pyrimidyl-triazines (where ring D is atriazine) and 5-membered D ring-C rings, generally referred to herein asthe C-D ring portion of the compounds of Formulas I-III, can be preparedaccording to the method generally described in Scheme 1. As shown,Suzuki coupling methodology utilizing an aryl halide (1) where X is ahalide such as iodide, bromide or chloride, and an aryl borinate (2) inthe presence of palladium, such as Pd(PPh₃)₄, and a weak base, such as aNa₂CO₃, K₂CO₃ or NaHCO₃ in a polar solvent such as DME can be used tosynthesize compound (3). LG is a known leaving group, such as F, Br, Ior Cl. Similarly, other known aryl coupling methods, such as use ofstannanes, zincates and copper coupling techniques are also suitable toprepare compound (3).

In a similar manner, phenyl-pyridines, phenyl-pyrimidines andphenyl-triazine C-D rings of the compounds of Formulas I-III, can alsobe prepared according to the Suzuki or other metallation chemistrymethods, wherein the aryl borinate (2) is a desirably substituted phenylborinate, as described in Scheme 1.

Alternatively, amino-substituted pyridyl pyrimidines C-D ring systems(8) can be prepared according to the method shown in scheme 2.

Chloro-nicotinic acid chlorides (4) can be treated with dimethylmalonatein the presence of a suitable base and MgCl to form intermediate (5).Compound (5) can be cyclized to form the hydroxyl-substitutedpyrimidyl-pyridine compound (6), in the presence of suitable base andformamidine acetate. Desirable amino-R¹ groups can be installed at the 3position of the 4,6-pyrimidine D-ring by simply treating compound (7)with a primary or secondary amine, having the desired substitution, withheat under conditions milder than those required to displace the pyridylchloride of compound (6). Further, compound (6) can be treated withp-toluene sulfonyl chloride, or other similar activating reagents torender the pyrimidine hydroxyl group into a suitable leaving group (LG)for displacement with a desired, sufficiently reactive nucleophile,including amines, sulfur, and oxygen nucleophiles. Also, compound (6)may be treated with a base sufficiently strong to deprotonate thehydroxyl proton in order to alkylate the hydroxyl group, thereby formingan ether, alkoxy moiety, and the like. Further, compound (6) can beconverted to the corresponding thiol utilizing reactions and techniquesknown in the art. This thiol (not shown0 may then be converted tocorresponding thio-linked R¹ groups. In addition, compound (7) can betreated with ammonia to give the amino adduct, which then can bealkylated, acylated, or otherwise substituted with a desired group. Suchmethods are known to those skilled in the art, and are described inJerry March's Advanced Organic Chemistry, 4^(th) edition (1992), whichdisclosure is hereby incorporated by reference in its entirety.

The 2,4-regioisomer of the above pyridyl-pyrimidines can also be madeusing the following Scheme 3.

Compound (10) can be made by treating the acid chloride of compound (9a)(ring C) and converting it to the corresponding methyl ketone (9b)followed by treatment with dimethyl formamide dimethylacetal to obtainthe corresponding enaminone (9c). Then substituted guanidine.HCl can betreated with a suitable base, such as sodium methoxide, for a timeperiod prior to exposing the guanidine mixture to the enaminone (9c) toform the pyridyl pyrimidine (10). This method allows desired R¹ groupsto be installed prior to ring closure. Care must be taken to restrictthe R¹ groups in this method to those, which would not interfere with orreact during formation of intermediates 9a-9c and also ring closure toform compound (10), as appreciated by persons of ordinary skill in theart.

Alternatively, compound (9c) can be treated with guanidine.HCl in thepresence of NaOH in isopropanol to afford the corresponding3-amino-pyrimidine D ring (not shown, where R¹ is NH₂). The R¹ positionof this intermediated can be modified using reductive alkylation methodswith corresponding aldehydes, acylation methods, and other groups, bymethods appreciated by persons of ordinary skill in the art, to installthe desired groups at this position on the D ring of compounds ofFormulas I-III. Alternatively, the 3-aminopyrimidine may be converted to3-fluoropyrimidine with use of t-butyl nitrate and H-pyridine, and thefluoride then displaced with a desired R¹ group such as NH₂R, OR and SR.This latter technique may also be used to convert amino-triazines to thecorresponding fluoro-triazines.

Similarly, pyridyl-triazines C-D biaryl ring systems can be made usingthe method of scheme 4.

In a manner similar to the method illustrated and described in Scheme 2,desirable amino-R¹ groups can be installed at the 3 position of atriazine D ring by treating compound (15) with a primary or secondaryamine, having the desired substitution, with heat under conditions lessstrenuous than required to displace the pyridyl chloride of compound(15).

The C-D ring portion of the compounds of Formulas I-III can be attachedto the B ring of compound (17—see scheme 5 below) by a number ofconventional methods known in the art, as disclosed in March. Suitablemethods are illustrated in schemes 5 and 6 below.

As shown in Scheme 5, compound (18 or 18a) comprising biaryl ethers andthiols (where L¹=O and S, respectively) can be prepared by reactingcompound (16) (where LG is a leaving group, such as a halide, like achlorine or bromine) with a nucleophilic phenyl compound (17) wherein Cis a suitable nucleophile, such as NHR or NH₂ (Scheme 6), OH, SH orcarbon nucleophile, sufficient to displace the chloride from ring C ofcompound (16). For example, phenols (L¹=O) and thiols (L¹=S) can becoupled with activated aryl chlorides to form the biaryl ethers andthiols (compound 18) using weak bases such as TEA, or inorganic basessuch as Cs₂CO₃, in DMSO at elevated temperatures, such as ranging formabout 70° C. to about 130° C. Similarly, this transformation can also becarried out in NMP at about 200° C. in a microwave.

Anilines (compound 17 or 17a) can be coupled with activated arylchlorides (compound 16) to form biaryl anilines (compound 18 or 18a)using Pd catalysis or NEt₃.TFA under suitable conditions, which may ormay not require the input of heat.

Alternatively, and with reference to Scheme 2, where certain R¹ and/orR² groups hinder or limit the ability to couple ring C to ring B via thenucleophilic displacement method described above, the B-C ring couplingcan be accomplished from intermediate compound (6) in Scheme 2 asfollows in Scheme 7.

As shown, compound (16) can first be reacted with the desired B ringnucleophilic species prior to converting the D-ring hydroxyl group tothe corresponding chloride for subsequent displacement with an amine, orother desired R¹⁵ group.

Compounds of the invention (Formulas I-III) wherein D is CR¹² can beprepared by the general method shown in scheme 8.

Compounds of the invention (Formulas I-III) wherein C¹ is CR¹⁰ can beprepared by the general method shown in scheme 8.

As shown, commercially available 2-hydroxynicotinic acid can beiodinated and subjected to thionyl chloride according to the proceduredisclosed in Elworthy et al., J. Med. Chem., 40 (17):2674-2687 (1997),which disclosure is incorporated herein by reference in its entirety.Conversion of the iodinated intermediate (compound 22) to thecorresponding pyrimidine (compound 23) proceeds as described above inScheme 2. After displacement of the pyridyl chloride (compound 23) withan aniline (compound 17) to form compound (24), Pd(0) mediated-couplingwith an aryl boronate in the presence of mild base, such as sodium orpotassium carbonate or bicarbonate, in toluene affords compound (25), anaryl pyridyl pyrimidine. Compound (25) can also be prepared usingcorresponding stannanes or zincates, as known in the art. Alternatively,desired R¹⁰ groups may be installed onto the C-ring via the iodide,using conventional methods (not shown), as appreciated by those skilledin the art.

Alternatively, the desired aryl group can be installed on ring C(compound 20) even before building the D-C ring piece of compounds ofFormulas I-III. For example, Church et al. describes the synthesis of5-aryl-2-chloropyridines from phenylacetic acids in J. Org. Chem.,60:3750-3758 (1995), which disclosure is incorporated herein byreference in its entirety.

The examples described hereinafter represent exemplary methods ofsynthesizing or preparing desired compounds of Formulas I-III,intermediates and starting building blocks thereof, including exemplaryA rings, B rings, A-B rings, C-D rings, B-C-D rings and fragmentsthereof. It should be appreciated that these methods are merelyrepresentative examples and other conventional, known or developedalternative methods may also be utilized. It should also be appreciatedthat the exemplary compounds are merely for illustrative purposes onlyand are not to be construed as limiting the scope of this invention inany manner.

Analytical Methods:

Unless otherwise indicated, all HPLC analyses were run on a AgilentModel 1100 system with an Agilent Technologies Zorbax SB-C₈(5μ) reversephase column (4.6×150 mm; Part no. 883975-906) run at 30° C. with a flowrate of about 1.50 mL/min. The mobile phase used solvent A (H₂O/0.1%TFA) and solvent B (AcCN/0.1% TFA) with a 11 min gradient from 5% to100% AcCN. The gradient was followed by a 2 min return to 5% AcCN andabout a 2.5 minute re-equilibration (flush).

LC-MS Method:

Samples were run on a Agilent model-1100 LC-MSD system with an AgilentTechnologies XDB-C₈ (3.5μ) reverse phase column (4.6×75 mm) at 30° C.The flow rate was constant and ranged from about 0.75 mL/min to about1.0 mL/min.

The mobile phase used a mixture of solvent A (H₂O/0.1% HOAc) and solventB (AcCN/0.1% HOAc) with a 9 min time period for a gradient from 10% to90% solvent B. The gradient was followed by a 0.5 min period to returnto 10% solvent B and a 2.5 min 10% solvent B re-equilibration (flush) ofthe column.

Preparative HPLC Method:

Where indicated, compounds of interest were purified via reverse phaseHPLC using a Gilson workstation with a 20×50 mm column at 20 mL/min. Themobile phase used a mixture of solvent A (H₂O/0.1% TFA) and solvent B(AcCN/0.1% TFA) with a 10 min gradient from 5% to 100% solvent B. Thegradient is followed by a 2 min return to 5% AcCN.

Proton NMR Spectra:

Unless otherwise indicated, all ¹H NMR spectra were run on a Varianseries Mercury 300 MHz or on a Bruker 400 MHz instrument. Where socharacterized, all observed protons are reported as parts-per-million(ppm) downfield from tetramethylsilane (TMS) or other internal referencein the appropriate solvent indicated.

Example 1

Synthesis of 2-chloro-4-(2-chloro-pyridin-3-yl)-[1,3,5]triazine Step 1:Preparation of 2-chloro-nicotinamidine

2-Chloro-3-cyanopyridine (5.0 g, 36 mmol) was dissolved in dry EtOH (100mL) at 0° C. HCl was bubbled through the mixture for 3 h and the mixturewas sealed and refrigerated (about 8° C.) overnight. Afterconcentration, the residue was stirred with ammonium acetate (5.5 g) in100 mL IpOH. After 12 h, the pH was adjusted to 9 (from 4) usingconcentrated NH₄OH solution, and stirring continued two more days. Themixture was concentrated and purified by flash chromatography (10:1:0.1CH₂Cl₂/MeOH/NH₄OH). Trituration in hot tBuOMe/IpOH removed some residualamide side-product to provide the product as a white solid.

Step 2: Preparation of amino-(2-chloro-pyridin-3-yl)-methylcyanamide

2-Chloro-nicotinamidine was suspended in 10 mL IpOH with 500 mg solidcyanamide and the stirring solids were dissolved by addition of 5%aqueous NaHCO₃ (30 mL). After two days stirring, theamino-(2-chloro-pyridin-3-yl)-methylcyanamide was isolated by EtOAcextraction of the aqueous reaction mixture followed by flashchromatography using 95:5:0.5 CH₂Cl₂/MeOH/NH₄OH. MS m/z=181 [M+H]⁺.Calc'd for C₇H₆N₄Cl: 181.03.

Step 3: Preparation of2-chloro-4-(2-chloro-pyridin-3-yl)-[1,3,5]-triazine

Amino-(2-chloro-pyridin-3-yl)-methylcyanamide (3.5 g) was added as asolid to a stirring, 0° C. solution of POCl₃ (2.3 ml, 25 mmol) and DMF(1.9 mL, 25 mmol) in 100 mL AcCN. The clear solution was stirred at RTfor 1 h. Toluene (40 mL) was added and the mixture was concentrated. Theresidue was immediately filtered through a 200 g plug of silica (loadingin 10:1 CH₂Cl₂/IpOH, eluting with 10:1->4:1 hexane/t-BuOMe).Concentration provided2-chloro-4-(2-chloro-pyridin-3-yl)-[1,3,5]triazine as a white solid. MSm/z=227 [M+H]⁺. Calc'd for C₈H₄Cl₂N₄: 225.98.

Example 2

Synthesis of [4-(2-Chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]methyl-amine

To 2-chloro-4-(2-chloro-pyridin-3-yl)-[1,3,5]triazine (10.0 g, 44.0mmol) in 55 ml of methylene chloride was added methylamine (45 ml, 88.0mmol) as a 2.0 M solution in THF at 0° C. After stirring at roomtemperature for 18 h, the mixture was diluted with acetone and filteredthrough a plug of silica gel and concentrated to yield the desiredproduct. MS m/z=222 [M+H]⁺. Calc'd for C₉H₈ClN₅: 221.65.

Example 3

Synthesis of 4-(2-Chloro-pyridin-3-yl)-pyrimidine Step 1. Preparation of1-(2-Chloro-pyridin-3-O-3-dimethylamino-propenone

1-(2-Chloro-pyridin-3-yl)-ethanone (21.7 g, 139 mmol) in 46 mLN,N-dimethylformamide, dimethyl acetal (42 g, 350 mmol) was heated undera drying tube at 85° C. for 1.5 h and concentrated. The residue waspurified by suction filtration chromatography (using 150 g silica in aBuchner funnel, with rapid collection of fractions eluting with 10:1 andthen 5:1 CH₂Cl₂/IpOH) to provide yellow solid product. MS m/z=211[M+H]⁺. Calc'd for C₁₀H₁₁ClN₂O: 210.66.

Step 2. Preparation of 4-(2-Chloro-pyridin-3-yl)-pyrimidine

Sodium methoxide was generated over a period of 1.5 h by theintermittent addition of small chunks of sodium metal (8.3 g total, 360mmol) to 400 mL dry methanol under N₂ at room temperature, using a bathof 500 mL IpOH at room temperature as a heat sink. Formamidine acetate(42.7 g, 410 mmol) was added, followed ten minutes later by theenaminone (30.6 g, 146 mmol). The reaction was stirred overnight under aN₂-filled balloon at an internal temperature of 40° C. After 20 h, themixture was stirred at 48° C. for 4 h. Additional formamidine acetate(7.0 g) was added and the mixture was stirred overnight at 44° C. Themixture was concentrated by rotary evaporator, taken up in ethyl acetateand extracted with saturated aqueous NaHCO₃. The aqueous layer wasback-extracted with EtOAc. The combined organic layers (1.2 L) weredried over Na₂SO₄ and concentrated. The residue was purified by flashvacuum filtration chromatography (300 g silica) in 3:1 to 2:1hexane/EtOAc to provide white solid product. MS m/z=192 [M+H]⁺. Calc'dfor C₉H₆ClN₃: 191.62.

Example 4

Synthesis of 4-(2-chloropyridin-3-yl)-N-methylpyrimidin-2-amine Step 1.Preparation of 1-(2-Chloro-pyridin-3-yl)-3-dimethylamino-propenone

The title compound was prepared according to the procedure in Example 3,step 1.

Step 2. Preparation of4-(2-chloropyridin-3-yl)-N-methylpyrimidin-2-amine

Sodium metal (3.40 g, 148 mmol) was added over ˜10 minutes to 180 mL ofMeOH at RT and allowed to stir for an additional 30 minutes to generatesodium methoxide. Methyl guanidine HCl (20.0 g, 182 mmol) was added andthe resulting mixture was stirred for 30 minutes before1-(2-Chloro-pyridin-3-yl)-3-dimethylamino-propenone (12.0 g, 57 mmol)was added. An air condenser was attached and the mixture was heated to50° C. for 23 hours. Part of the MeOH was removed by rotary evaporationand the resulting solid was filtered and washed with saturated sodiumbicarbonate and water. The desired product was obtained as a fluffywhite solid after drying. MS m/z=221 [M+H]⁺. Calc'd for C₁₀H₉ClN₄:220.66.

Example 5 4-(2,5-dichloropyridin-3-yl)-N-methylpyrimidin-2-amine

The title compound was prepared in a manner analogous to that describedin Example 4. MS m/z=255, 257 [M+H]⁺; Calc'd for C₁₀H₈Cl₂N₄: 255.11.

Example 6 4-(2-chloropyridin-3-yl)-5-fluoro-N-methylpyrimidin-2-amine

The title compound was prepared in a manner analogous to that describedin Example 4. MS m/z=238 [M+H]⁺. Calc'd for C₁₀H₈ClFN₄: 238.65.

Example 7

Synthesis of 4-(2-Chloropyridin-3-yl)-2-(methylthio)pyrimidine

The 5 L reactor was purged with Argon then charged with4-chloro-2-methyl-thiopyrimidine (111 mL, 953 mmol) and2-choropyridine-3-boronic acid (100 g, 635 mmol). The reactor was putunder vacuum and filled with Argon. This was repeated two more times.Ethylene glycol dimethyl ether (500 mL) was added to the mixturefollowed by Pd(PPh₃)₄ (58.7 g, 50.8 mmol). The reactor was put undervacuum and filled with Argon. This was repeated two more times then moreethylene glycol dimethyl ether (1500 mL) was added. A solution of sodiumbicarbonate (1M soln, 1300 mL) was added to the stirred reactionmixture. A small exotherm was observed. The reaction mixture was stirredand refluxed for 2.75 h then gradually cooled to 25° C. The mixture wasdiluted with ethyl acetate (1500 mL) and vigorously stirred. The layerswere allowed to separate the aqueous phase was removed. The organicphase was washed with water (1000 mL), then brine (1000 mL), dried overmagnesium sulfate and filtered. The solvents were removed under vacuumto afford the crude product as a light yellow solid. The crude productwas separated by column chromatography using a mixture of ethanol anddichloromethane. The product was obtained as a white solid and wasslurried in ethyl acetate to remove traces of an impurity. The titlecompound was obtained as a white fluffy solid. MS m/z=238 [M+H]⁺. Calc'dfor C₁₀H₈ClN₃S: 237.71.

Example 8

Synthesis of 2-Chloro-4-(2-chloropyridin-3-yl)pyrimidine

To 2,4-dichloropyrimidine (2.00 g, 13.4 mmol), 2-choropyridine-3-boronicacid (3.16 g, 20.1 mmol) and Pd(PPh₃)₄ (1.55 g, 1.30 mmol), was addedDME (30.0 mL) and 1 M NaHCO₃ (13.0 mL). The resulting mixture was heatedto 90° C. for 17 hours, then diluted with EtOAc and extracted withsaturated sodium carbonate, water, and brine. The organics were driedover sodium sulfate, filtered and concentrated. The resulting solid wastriturated with ether and dried to yield the desired product. MS m/z=226[M+H]⁺. Calc'd for C₉H₅Cl₂N₄: 225.12.

Example 9

Synthesis of4-(2-chloropyridin-3-yl)-N-(3-morpholinopropyl)pyrimidin-2-amine

To 2-chloro-4-(2-chloropyridin-3-yl)pyrimidine (100 mg, 0.44 mmol) andpotassium carbonate (122 mg, 0.88 mmol) was added DMSO (1.0 mL) and3-morpholinopropan-1-amine (77 mg, 0.53 mmol). The resulting mixture washeated for 15 hours at 80° C. The cooled reaction was diluted with EtOAcand extracted with water. The organic layer was dried over sodiumsulfate, filtered and concentrated to yield the desired product as ayellow oil. MS m/z=334 [M+H]⁺. Calc'd for C₁₆H₂₀ClN₅O: 333.84.

Example 10

Synthesis of4-(2-chloropyridine-3-yl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3,b]pyridineStep 1. Preparation of4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine

Sodium hydride (880 mg, 22 mmol, 1.1 equiv, 60% in mineral oil) waswashed with 15 mL of dry hexanes under an argon atmosphere. The hexaneswas removed and replaced with 40 mL of THF. 4-Chloro-7-azaindole wasadded portionwise into the sodium hydride suspension. The suspension wasstirred until the gas evolution ceased. Triisopropylchlorosilane (3 g,20 mmol, 1 equiv) was added via syringe. The reaction was placed in apreheated oil bath at 80° C. and monitored by LC-MS and TLC. After 3hours, the reaction was cooled to room temperature. The reaction wasquenched slowly with saturated NH₄Cl. The product was extracted withhexanes and Et₂O. The organic layers were combined, washed with brine,dried over MgSO₄, and concentrated. The residue was passed through aplug of silica gel with an aid of hexanes to remove the baseline spots.The filtrate was concentrated to afford4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine as a viscouscolorless oil. ¹H NMR (Varian, 300 MHz, CDCl₃) ppm: 8.14 (d, J=5 Hz,1H), 7.32 (d, J=3.6 Hz, 1H), 7.05 (dd, J=5, 0.8 Hz, 1H), 6.64 (dd,J=3.5, 0.8 Hz, 1H), 1.87 (sept, J=7.3 Hz, 3H), 1.10 (d, J=7.3 Hz, 18H).

Step 2. Preparation of4-(2-chloropyridine-3-yl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3,b]pyridine

4-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (5.03 g, 16.3mmol, 1 equiv), 2-chlorpyridine-3-boronic acid (4.36 g, 27.7 mmol, 1.7equiv), palladium acetate (183 mg, 0.815 mmol, 5 mol %),2-(dicyclohexylphosphino)biphenyl (571 mg, 1.63 mmol, 10 mol %), andfinely ground anhydrous K₃PO₄ (10.4 g, 48.9 mmol, 3 equiv) were addedinto a sealed tube. The tube was purged with argon for 5 minutes.Dioxane (30 mL) was added via syringe under a positive argon flow. Thetube was sealed and the reaction was stirred at RT for 5 minutes. Thenthe tube was placed in a preheated oil bath at 110° C. for 2 h. Thereaction was cooled down to room temperature. The content was filteredthrough a plug of celite with an aid of diethyl ether. The filtrated wasconcentrated under reduced pressure. The product was purified by columnchromatography using a mixture of 95:5 Hex:Et₂O as eluent. The product,4-(2-chloropyridine-3-yl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3,b]pyridinewas obtained as a light yellow solid. ¹H NMR (Varian, 300 MHz, CDCl₃)ppm: 8.35 (d, J=4.7 Hz, 1H), 8.30-8.28 (m, 1H), 8.10-8.03 (m, 1H),7.40-7.30 (m, 2H), 7.15 (dd, J=4.3, 1.7 Hz, 1H), 6.54 (dd, J=3.6, 1.9Hz, 1H), 1.89 (sept, J=7.4 Hz, 3H), 1.15 (d, J=7.4 Hz, 18H).

Example 11

Synthesis of 2-Chloro-2′-fluoro-[3,4′]bipyridinyl

To 2-fluoro-4-iodopyridine (9.45 g, 42.4 mmol),2-chloropyridine-3-boronic acid (10.0 g, 63.5 mmol), Na₂CO₃ (13.5 g, 127mmol), Pd(OAc)₂ (480 mg, 2.12 mmol) and P(tBu)₃.HBF₄ (1.23 g, 4.24 mmol)was added dioxane (125 mL) and water (45 mL). The mixture was heatedovernight at 100° C. in a sealed tube. The resulting mixture was dilutedwith EtOAc and extracted with water and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The resulting solid wastriturated with n-Hexanes and dried to yield2-chloro-2′-fluoro-[3,4′]bipyridinyl. MS m/z=209 [M+1]⁺. Calc'd forC₁₀H₆ClFN₂: 208.62.

Example 12

Synthesis of (2-Chloro-[3,4′]bipyridinyl-2′-yl)-methyl-amine

To 2-chloro-2′-fluoro-[3,4′]bipyridinyl (5.30 g, 25.4 mmol), methylaminehydrochloride (9.00 g, 133 mmol) and K₂CO₃ (28.1 g, 203 mmol) was addedDMSO (70 mL). The mixture was heated overnight at 80° C. in a sealedtube. The cooled mixture was diluted with water (300 mL) and theresulting solid was filtered, washed with water and dried to yield(2-chloro-[3,4′]bipyridinyl-2′-yl)-methyl-amine. MS m/z=220 [M+1]⁺.Calc'd for C₁₁H₁₀ClN₃: 219.68.

Example 13

Synthesis of 4-(2-fluoropyridin-3-yl)pyridin-2-amine

A pressure vessel was charged with 6.35 mL of water and degassed withnitrogen for 0.5 h. To this vessel was added potassium acetate (2.31 g,23.5 mmol), 2-fluoropyridine-3-boronic acid (2.48 g, 17.6 mmol),4-chloropyridin-2-amine (1.51 g, 11.7 mmol),dichloro-bis(di-tert-butylphenylphosphino)Pd(II) (0.146 g, 0.235 mmol)and 58.5 mL CH₃CN. The mixture was purged under nitrogen for severaladditional minutes, and the pressure bottle was sealed. The reactionmixture was heated to 85° C. for 15 h. Upon cooling the layers wereseparated, and the organic portion was dried with Na₂SO₄ andconcentrated. The resulting solid was triturated with ethylacetate/diethyl ether to provide 4-(2-fluoropyridin-3-yl)pyridin-2-amineas a tan solid. MS m/z=190 [M+H]⁺. Calc'd for C₁₀H₈FN₃: 189.19.

Example 14

Synthesis of 4-(2-chloropyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine Step 1.Preparation of 4-iodo-1H-pyrazolo[3,4-b]pyridine

To 2-fluoro-4-iodonicotinaldehyde (11.33 g, 45.1 mmol) in THF (200 mL)was added hydrazine (5.67 ml, 181 mmol) dropwise. The resulting mixturewas stirred at RT under a nitrogen atmosphere for 5 h. The reaction wasconcentrated, diluted with 10:1 acetone/MeOH and filtered through a padof silica gel. Removed most of the solvent in vacuo, then diluted withsome hexanes and filtered resulting solid. Dried to yield4-iodo-1H-pyrazolo[3,4-b]pyridine as an off-white solid. MS m/z=246[M+1]⁺. Calc'd for C₆H₄₁N₃: 245.02.

Step 2. Preparation of tert-butyl4-iodo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate

To 4-iodo-1H-pyrazolo[3,4-b]pyridine (1.110 g, 4.53 mmol), di-t-butyldicarbonate (1.09 g, 4.98 mmol), and N,N-dimethylpyridin-4-amine (0.277g, 2.27 mmol) was added methylene chloride (15 mL). The resultingmixture was stirred at RT under a nitrogen atmosphere for 15 h, dilutedwith methylene chloride and extracted with saturated sodium bicarbonate.Dried organics over sodium sulfate, filtered through a pad of silica gelusing 1:1 EtOAc/CH₂Cl₂ and concentrated to yield tert-butyl4-iodo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate as a light yellow solid.¹HNMR (Bruker, 400 MHz, DMSO-d₆) ppm: 8.42 (m, 2H), 7.98 (m, 1H), 1.72(s, 9H).

Step 3. Preparation of4-(2-chloropyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine

To tert-butyl 4-iodo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (1.00 g,2.90 mmol), 2-chloropyridin-3-ylboronic acid (1.14 g, 7.24 mmol), andsodium carbonate (1.23 g, 11.6 mmol) was added dioxane (10 mL) and water(4 mL). The mixture was stirred at RT for 5 minutes, thentri-t-butylphosphonium tetrafluoroborate (0.084 g, 0.290 mmol) andpalladium(II) acetate (0.033 g, 0.145 mmol) were added and the mixturewas heated to 100° C. in a sealed tube for 23 hours. The reaction wasdiluted with EtOAc and extracted with 1N sodium bicarbonate. Theorganics were dried over sodium sulfate, filtered and concentrated. Thecrude was purified by ISCO silica gel chromatography (10-90%EtOAc/hexanes; 80 g column) and product fractions were concentrated toyield 4-(2-chloropyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine as a whitesolid. MS m/z=231 [M+1]⁺. Calc'd for C₁₁H₇ClN₄: 230.66.

Example 15

Synthesis of 4-(2-chloropyridin-3-yl)pyrimidin-2-amine

In an argon purged 500 mL round bottom flask placed in an isopropanolbath, was added sodium metal (3.40 g, 148 mmol) slowly to methanol (180mL). The mixture was stirred at RT for about 30 minutes. To this wasadded guanidine hydrochloride (12.0 mL, 182 mmol) and the mixture wasstirred at RT for 30 minutes, followed by addition of(E)-1-(2-chloropyridin-3-yl)-3-(dimethylamino)prop-2-en-1-one (12.0 g,57.0 mmol), attached air condenser, moved reaction to an oil bath, whereit was heated to about 50° C. for 24 h. Approximately half of themethanol was evaporated under reduced pressure and the solids werefiltered under vacuum, then washed with saturated NaHCO₃ and H₂O, airdried to yield 4-(2-chloropyridin-3-yl)pyrimidin-2-amine as off whitesolid. MS m/z=207 [M+1]⁺. Calc'd for C₉H₇ClN₄: 206.63.

Example 16

Synthesis of 4-(2-chloropyridin-3-yl)-1H-pyrazol-3-amine Step 1.Preparation of (2-chloropyridin-3-yl)methanol

To a stirred solution of 2-chloronicotinic acid (8.00 g, 51.0 mmol) inTHF (120 mL) at 0° C. under nitrogen was slowly added lithiumtetrahydroaluminate (51 mL, 51 mmol) over five minutes. The reaction wasallowed to warm to RT over 2 h and was monitored by TLC. The reactionwas quenched by addition of small amounts of ice followed by water.Extracted product into EtOAc, washed 2×H₂O, 1×NaCl, dried with Mg₂SO₄,filtered through fritted funnel, and concentrated the solution to yield(2-chloropyridin-3-yl)methanol as an orange oil. Used without furtherpurification.

Step 2. Preparation of 3-(bromomethyl)-2-chloropyridine

In a 250 mL round bottom flask was dissolved(2-chloropyridin-3-yl)methanol (6.7 g, 47 mmol) in CH₂Cl₂ (100 mL). Thereaction was cooled to 0° C., to which was slowly addedtribromophosphine (4.8 mL, 51 mmol), and allowed to warm to RTovernight. The reaction was quenched by addition of ice, extracted intoCH₂Cl₂, washed 1×NaHCO₃, 2×H₂O, dried with Mg₂SO₄, filtered throughfritted funnel and filtrate was concentrated. The crude was purified bysilica gel chromatography eluting with 15-45% EtOAc/Hex. The productfraction were concentrated down to yield3-(bromomethyl)-2-chloropyridine as off-white solid. MS m/z=206, 208[M+1]⁺. Calc'd for C₆H₅BrClN, 206.47.

Step 3. Preparation of 2-(2-chloropyridin-3-yl)acetonitrile

In a 250 mL round bottom flask was dissolved3-(bromomethyl)-2-chloropyridine (7.2 g, 35 mmol) in MeOH (70 mL). Tothe solution was added sodium cyanide (3.4 g, 70 mmol), then attached areflux condenser, stirred the mixture at 80° C., while monitoring thereaction by LCMS. After about 1.5 h, the reaction was cooled to RT,concentrated, diluted with EtOAc, upon which a white solid crashed out.The solids were filtered and rinsed with EtOAc. The organic filtrate wasconcentrated to yield a crude reddish brown solid. The solid wasdissolved in EtOAc, and purified by silica gel chromatography elutingwith 40-70% EtOAc/Hexanes. The product fractions were concentrated toyield 2-(2-chloropyridin-3-yl)acetonitrile as an off-white solid. MSm/z=153 [M+1]⁺. Calc'd for C₇H₅ClN₂: 152.58.

Step 4. Preparation of 2-(2-chloropyridin-3-yl)-3-oxopropanenitrile

A solution of 2-(2-chloropyridin-3-yl)acetonitrile (2.0 g, 13 mmol) inTHF (5 mL) was slowly added to a suspension of sodium hydride, 60% inmineral oil (1.31 g, 33.0 mmol) in THF (10 mL) at 0° C. The mixture wasstirred for 15 minutes, and ethyl formate (1.1 mL, 13 mmol) was slowlyadded. The mixture was stirred at RT, and monitored by LCMS. Uponcompletion, the reaction was extracted into EtOAc, washed organics2×H₂O, dried with Mg₂SO₄, filtered through fritted funnel, andlyophilized to yield 2-(2-chloropyridin-3-yl)-3-oxopropanenitrile asreddish brown solid. The crude was used without further purification. MSm/z=181 [M+1]⁺. Calc'd for C₈H₅ClN₂O: 180.59.

Step 5. Preparation of 4-(2-chloropyridin-3-yl)-1H-pyrazol-3-amine

In a 150 mL sealed tube, added2-(2-chloropyridin-3-yl)-3-oxopropanenitrile (2.5 g, 14 mmol), water(2.0 mL, 14 mmol), acetic acid (14 mL, 14 mmol), ethanol (28 mL, 14mmol), 1,4-dioxane (14 mL), and anhydrous hydrazine (0.40 ml, 14 mmol).The mixture was stirred at 70° C. for 20 minutes. The reaction wascooled to RT and concentrated. The concentrate was extracted into EtOAc,washed 1×NaHCO₃, 1×H₂O, dried over Mg₂SO₄, filtered through frittedfunnel and concentrated. The crude was purified using reverse phasechromatography. The product was extracted into CH₂Cl₂ washed 1×NaHCO₃1×H₂O, dried with Na₂SO₄, filtered through fritted funnel, concentratedto yield 4-(2-chloropyridin-3-yl)-1H-pyrazol-3-amine as tan solid. MSm/z=195 [M+1]⁺. Calc'd for C₈H₇ClN₄: 194.62.

Example 17

Synthesis of 1,4-dichloro-5,8-difluorophthalazine Step 1: Preparation of5,8-difluoro-2,3-dihydrophthalazine-1,4-dione

To 4,7-difluoroisobenzofuran-1,3-dione (1.00 g, 5.43 mmol) and sodiumacetate (0.535 g, 6.52 mmol) was added water (14 mL), acetic acid (7.15ml, 125 mmol) and hydrazine (0.205 ml, 6.52 mmol) (slowly). A watercondenser was attached and the mixture was heated to reflux for 20hours. Cooled to RT and filtered the resulting solid. Washed with waterand dried to yield 5,8-difluoro-2,3-dihydrophthalazine-1,4-dione as awhite solid. MS m/z=199 [M+1]⁺. Calc'd for C₈H₄P₂N₂O₂: 198.13.

Step 2: Preparation of 1,4-dichloro-5,8-difluorophthalazine

To 5,8-difluoro-2,3-dihydrophthalazine-1,4-dione (0.860 g, 4.34 mmol)was added phosphorus oxychloride (4.05 ml, 43.4 mmol). A water condenserwas attached and the resulting mixture was heated to reflux for 15.5hours. Cooled the reaction and concentrated in vacuo. Diluted thereaction with methylene chloride and ice water, then quenched with solidsodium bicarbonate until pH was basic. The layers were separated andorganics dried over sodium sulfate, filtered and concentrated to yield1,4-dichloro-5,8-difluorophthalazine as a light yellow solid. MSm/z=235, 237 [M+1]⁺. Calc'd for C₈H₂Cl₂F₂N₂: 235.02.

The following intermediates were prepared by a method analogous to thatdescribed in Example 17 above.

Example 18 1,4-dichloro-6,7-difluorophthalazine

MS m/z=235, 237 [M+1]⁺. Calc'd for C₈H₂Cl₂F₂N₂: 235.02.

Example 19 5,8-dichloropyrido[3,2-d]pyridazine

MS m/z=200, 202 [M+1]⁺. Calc'd for C₇H₃Cl₂N₃: 200.03.

Example 20 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine

MS m/z=189, 191 [M+1]⁺. Calc'd for C₇H₆Cl₂N₂: 189.05.

Example 21 1,4-dichloro-5,6,7,8-tetrahydrophthalazine;

MS m/z=203, 205 [M+1]⁺. Calc'd for C₈H₈Cl₂N₂: 203.07.

Example 22 3,6-dichloro-4,5-dimethylpyridazine

MS m/z=177, 179 [M+1]⁺. Calc'd for C₆H₆Cl₂N₂: 177.03.

Example 23

Synthesis of 5,8-dichloropyrazino[2,3-d]pyridazine Step 1. Preparationof 6,7-Dihydropyrazino[2,3-d]pyridazine-5,8-dione

The title compound was prepared according to a literature procedure(Paul, D. B. Aust. J. Chem. 1974, 27, 1331). As described therein,2,3-pyrazinedicarboxylic anhydride (5.00 g, 33.3 mmol), hydrazinehydrate (2.8 g, 56 mmol), and acetic acid (40.4 ml, 33.3 mmol) weremixed at RT. White precipitated crashed out. The reaction was heatedunder reflux for approximately 20 min. The reaction was cooled to RT andthe solids were filtered, washed with water, and dried under vacuum. Theproduct, 6,7-dihydropyrazino[2,3-d]pyridazine-5,8-dione was obtained aswhite solid. ¹H NMR (Bruker, 400 MHz, D₂O) ppm: 8.87 (s, 2H).

Step 2. Preparation of 5,8-Dichloropyrazino[2,3-d]pyridazine

The title compound was prepared according to a literature procedure(Patel, N. R.; Castle, R. N. J. Heterocyclic Chem. 1966, 3, 512). Amixture of 6,7-dihydropyrazino[2,3-d]pyridazine-5,8-dione (2.50 g, 15.2mmol), phosphorus pentachloride (6.98 g, 33.5 mmol), and phosphorusoxychloride (39.8 ml, 42.7 mmol) were added into a round bottom flaskequipped with a magnetic stir bar. A drying tube was attached on top ofthe condenser. The reaction was heated to reflux for 8 h. The orangesuspension was formed. The reaction was cooled to RT. The solvent wasazeotropically (toluene) removed under reduced pressure to remove excessPOCl₃. The black resulting residue was treated with ice and basifiedslowly with solid Na₂CO₃. The aqueous solution was extracted severaltimes with chloroform, the combined extracts were dried over MgSO₄,filtered, and concentrated to give product,5,8-dichloropyrazino[2,3-d]pyridazine. ¹H NMR (Bruker, 400 MHz, CDCl₃)ppm: 9.24 (s, 2H).

Example 24

Synthesis of 3,6-dichloro-4,5-bis(methoxymethyl)pyridazine

The title compound was made following the literature reference:Samaritoni, J G, Org. Prep. Proced. Int. 20, 117-121, 1988. To aslightly heterogeneous mixture of methoxyacetic acid (3.6 ml, 47 mmol),silver nitrate (0.57 g, 3.4 mmol), 3,6-dichloropyridazine (2.0 g, 13mmol), and concentrated sulfuric acid (1.7 ml, 20 mmol) in 30 mL waterat 70° C. was added a solution of ammonium persulfate (7.7 g, 34 mmol)in 15 mL water dropwise over ca. 10 min. The heterogeneous mixture wasallowed to stir for 30 min, at which point it was poured onto ice. Agummy gray solid was present. The aqueous material was filtered, and thecold filtrate was basified with conc. ammonium hydroxide. At pH 10, thesolution became dark yellow. The aqueous material was extracted threetimes with dichloromethane, dried over anhyd sodium sulfate, filtered,and concentrated in vacuo. The resulting yellow oil was purified bysilica gel chromatography (0-40% EtOAc/hexanes) to give3,6-dichloro-4,5-bis(methoxymethyl)pyridazine as a white solid. MSm/z=237 [M+H]⁺. Calc'd for C₈H₁₀Cl₂N₂O₂: 237.1.

Example 25

Synthesis of 1-Chloro-4-(4-methylthiophen-2-yl)phthalazine

1,4-Dichlorophthalazine (1.40 g, 7.03 mmol),4-methylthiophen-2-ylboronic acid (999 mg, 7.03 mmol), and PdCl₂(DPPF)(721 mg, 985 μmol) were added into a sealed tube. The tube was purgedwith Argon. Then sodium carbonate (2.0 M in water) (7.74 ml, 15.5 mmol)and 1,4-dioxane (35.2 ml, 7.03 mmol) were added. The tube was sealed,stirred at rt for 5 min, and placed in a preheated oil bath at 110° C.After 1 h, LC-MS showed product and byproduct (double coupling), and SMdichlorophthalazine. The reaction was cooled to rt, filtered through apad of celite with an aid of EtOAc, concentrated, and loaded ontocolumn. The product was purified by column chromatography using Hex toremove the top spot, then 80:20 Hex:EtOAc to collect the product. Theproduct, 1-chloro-4-(4-methylthiophen-2-yl)phthalazine was obtained asyellow solid. LC-MS showed that the product was contaminated with asmall amount of SM dichlorophthalazine and biscoupling byproduct. MSm/z=261 [M+1]⁺. Calcd for C₁₃H₉ClN₂S: 260.12.

Example 26

Synthesis of 1-chloro-4-phenyl-5,6,7,8-tetrahydrophthalazine

1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.270 g,0.369 mmol), phenylboronic acid (0.900 g, 7.38 mmol) and1,4-dichloro-5,6,7,8-tetrahydrophthalazine (2.25 g, 11.1 mmol) werecombined in a 150 mL sealable vessel under argon. 15 mL dioxane and 2.0M Sodium carbonate, aqueous (7.38 ml, 14.8 mmol) were added. The vesselwas sealed and heated to 80° C. to give a homogenous brown reaction.After 30 min, the reaction was cooled to ambient temperature and wasdiluted with EtOAc, water, and brine. The layers were separated, and theorganic layer was dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to give a red solid. This was taken up indichloromethane and purified by silica gel chromatography (0-60% EtOAcin hexanes) to give 1-chloro-4-phenyl-5,6,7,8-tetrahydrophthalazine asan off-white solid. MS m/z=245 [M+H]⁺. Calc'd for C₁₄H₁₃ClN₂: 244.7.

Example 27

Synthesis of 4-((4-phenylphthalazin-1-yl)methyl)phenol Step 1.Preparation of 2-(2-(4-methoxyphenyl)acetyl)-N-methylbenzamide

At 0° C., (4-methoxybenzyl)magnesium chloride (0.25 M in THF) (37 ml,9.3 mmol) was added to 2-methylisoindoline-1,3-dione (1.00 g, 6.2 mmol)in THF (3.0 mL) (Reference: Synthetic Comm. 2004, 34 (7), 1301-1308).The mixture was stirred at 0° C. for 5 minutes, then quenched with 10 mLof water. The reaction was warmed to RT and concentrated to yield2-(2-(4-methoxyphenyl)acetyl)-N-methylbenzamide as a white solid(crude). The material was carried on to next step without furtherpurification. MS m/z=284 [M+1]⁺. Calc'd for C₁₇H₁₇NO₃: 283.33.

Step 2: Preparation of 4-(4-methoxybenzyl)phthalazin-1(2H)-one

To 2-(2-(4-methoxyphenyl)acetyl)-N-methylbenzamide (1.76 g, 6.20 mmol)in EtOH (20 mL) was added hydrazine (3.50 ml, 112 mmol). A watercondenser was attached and the mixture was heated to reflux under anitrogen atmosphere for 5 days. After concentration, the reaction wasdiluted with EtOAc and extracted with water. The organics were driedover sodium sulfate, filtered and concentrated. The crude was purifiedby washing the resulting solid with diethyl ether and filtering to yield4-(4-methoxybenzyl)phthalazin-1(2H)-one as a white solid. MS m/z=267[M+1]⁺. Calc'd for C₁₆H₁₄N₂O₂: 266.30.

Step 3. Preparation of 1-(4-methoxybenzyl)-4-chlorophthalazine

To 4-(4-methoxybenzyl)phthalazin-1(2H)-one (1.18 g, 4.43 mmol) was addedphosphorus oxychloride (4.13 ml, 44.3 mmol). A water condenser wasattached and the mixture was heated to reflux under a nitrogenatmosphere for 15 hours. The reaction was concentrated in vacuo, dilutedwith methylene chloride and ice water, then quenched with solid sodiumbicarbonate until pH was basic and gas evolution ceased. The layers wereseparated and the organic layers were dried over sodium sulfate,filtered through a pad of silica gel using EtOAc and concentrated toyield 1-(4-methoxybenzyl)-4-chlorophthalazine as a light orange solid.MS m/z=285 [M+1]⁺. Calc'd for C₁₆H₁₃ClN₂O: 284.75.

Step 4. Preparation of 1-(4-methoxybenzyl)-4-phenylphthalazine

To 1,1′-bis(diphenylphosphoino)ferrocene-palladium dichloride (0.046 g,0.063 mmol), 1-(4-methoxybenzyl)-4-chlorophthalazine (0.360 g, 1.3mmol), and phenylboronic acid (0.39 g, 3.2 mmol) was added dioxane (4.0mL) and sodium carbonate (2.0M, aq) (1.9 ml, 3.8 mmol). The resultingmixture was heated to 100° C. in a sealed tube for 1 hour. The reactionwas diluted with EtOAc and extracted with water and brine. The organiclayers were dried over sodium sulfate, filtered, concentrated, and thecrude was purified by ISCO silica gel chromatography (10-100%EtOAc/hexanes, 40 g column). Concentrated the product fractions to yield1-(4-methoxybenzyl)-4-phenylphthalazine as a light yellow solid. MSm/z=327 [M+1]⁺. Calc'd for C₂₂H₁₈N₂O: 326.40.

Step 5. Preparation of 4-((4-phenylphthalazin-1-yl)methyl)phenol

To 1-(4-methoxybenzyl)-4-phenylphthalazine (0.240 g, 0.735 mmol) wasadded acetic acid (1.5 mL) followed by hydrobromic acid 48% (1.50 ml,27.6 mmol). A water condenser was attached and the mixture was heated toreflux for 3 hours. The reaction was diluted with water and neutralizedwith 6 N NaOH until pH˜6. Filtered the resulting solid, washed withwater and dried to yield 4-((4-phenylphthalazin-1-yl)methyl)phenol as anoff-white solid. MS m/z=313 [M+1]⁺. Calc'd for C₂₁H₁₆N₂O: 312.37.

Example 28

Synthesis of 7-chloro-4-phenylthieno[3,2-d]pyridazine Step 1.Preparation of 4-phenylthieno[2,3-d]pyridazin-7(6H)-one

To 3-benzoylthiophene-2-carboxylic acid (1.00 g, 4.31 mmol) and EtOH (15mL) was added hydrazine (1.35 ml, 43.1 mmol). A water condenser wasattached to the reaction flask and the mixture was heated to refluxunder nitrogen for 3.5 hours. The reaction was cooled to RT, theresulting solids filtered and washed with water, and dried to yield4-phenylthieno[2,3-d]pyridazin-7(6H)-one as a white solid. MS m/z=229[M+1]⁺. Calc'd for C₁₂H₈N₂OS: 228.27.

Step 2. Preparation of 7-chloro-4-phenylthieno[3,2-d]pyridazine

To 4-phenylthieno[2,3-d]pyridazin-7(6H)-one (0.714 g, 3.13 mmol) wasadded POCl₃ (2.92 ml, 31.3 mmol). A water condenser was attached to thereaction flask and the mixture was heated to reflux for 15.5 hours. Thereaction was concentrated and diluted with CH₂Cl₂ and ice water. Themixture was basified with solid sodium bicarbonate. The organic layerswere separated and dried over sodium sulfate. To the residual crudeafter concentration, 50% EtOAc was added and the solution was filteredthrough a pad of silica gel. The product fraction were concentrated toyield 7-chloro-4-phenylthieno[3,2-d]pyridazine as a light yellow solid.MS m/z=247 [M+1]⁺. Calc'd for C₁₂H₇N₂S: 246.71.

Example 29

Synthesis of 1-chloro-4-phenylphthalazine

A mixture of phosphoryl trichloride (28.4 ml, 310 mmol) and4-phenylphthalazin-1(2H)-one (13.8 g, 62.0 mmol) was heated overnightwith reflux condensor and drying tube in a 130° C. bath. The lightorange, homogeneous solution was cooled to ambient temperature andallowed to stand for several days. The reaction was poured onto stirringice carefully. The resulting mixture was brought to pH 8 by addition of6N NaOH carefully with addition of ice to control the temperature. Theresulting off-white solid was collected by filtration, air dried, anddried in vacuo to give as a light yellow solid.1-chloro-4-phenylphthalazine. MS m/z=241 [M+H]⁺. Calc'd for C₁₄H₉ClN₂:240.7.

Example 30

Synthesis of 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine

To a resealable tube was added 4-aminophenol (1.3 g, 12 mmol), cesiumcarbonate (7.8 g, 24 mmol), and DMSO (16 ml, 0.75 M). The mixture washeated to 100° C. for 5 minutes, and then4-(2-chloropyridin-3-yl)pyrimidin-2-amine (2.5 g, 12 mmol) was added,and the reaction mixture was heated to 130° C. overnight. Uponcompletion, as judged by LCMS, the reaction mixture was allowed to coolto RT and diluted with water. The resulting precipitate was filtered,and the solid washed with water and diethyl ether. The solid was thentaken up in 9:1 CH₂Cl₂:MeOH and passed through a pad of silica gel with9:1 CH₂Cl₂:MeOH as eluent. The solvent was concentrated in vacuo toprovide the desired product,4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine. MS m/z=280 [M+1]⁺.Calc'd for C₁₅H₁₃N₅O: 279.30.

Example 31

Synthesis of4-(2-((4-aminophenyl)sulfanyl)-3-pyridinyl)-N-methyl-2-pyrimidinamine

To 4-aminothiophenol (1.70 g, 13.6 mmol) and Cs₂CO₃ (8.90 g, 27.2 mmol)was added DMSO (18 mL). The mixture was stirred for 5 minutes at 100° C.before 4-(2-chloropyridin-3-yl)-N-methylpyrimidin-2-amine (3.00 g, 13.6mmol) was added. The resulting mixture was stirred for 16 hours at 130°C., then diluted with water and the resulting solid filtered. Afterwashing the solid with water and Et₂O it was dried under vacuum to yieldthe desired product as a tan solid. MS m/z=310 [M+1]⁺. Calc'd forC₁₆H₁₅N₃S: 309.40.

Example 32

Synthesis of 4-(3-(1H-pyrazol-4-yl)pyridin-2-yloxy)benzenamine Step 1.Preparation of 4-bromo-1-trityl-1H-pyrazole

In a 75 mL sealed tube, 4-bromopyrazole (1.0 g, 6.8 mmol), pyridine(21.0 mL, 258 mmol), triphenylmethyl chloride (2.1 g, 7.5 mmol), and4-dimethylaminopyridine (0.17 g, 1.4 mmol) were added. The mixture wasstirred at 80° C. for 24 hours. The mixture was diluted with water, andthe solids which crashed out were filtered, rinsed with water andair-dried to yield 4-bromo-1-trityl-1H-pyrazole as a white solid.

Step 2. Preparation of 2-chloro-3-(1-trityl-1H-pyrazol-4-yl)pyridine

To an argon purged 48 mL sealed pressure vessel was added 1,4-dioxane(2.6 mL), 4-bromo-1-trityl-1H-pyrazole (1.00 g, 2.60 mmol), potassiumfluoride (0.492 g, 8.48 mmol), 2-chloropyridine-3-boronic acid (0.808 g,5.14 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.176 g, 0.193mmol) and tri-t-butylphosphonium tetrafluoroborate (0.168 g, 0.578mmol). The vessel was purged with argon and heated to 100° C. for 5hours. The mixture was cooled to RT, filtered through a pad of silicagel using EtOAc and concentrated. The crude was purified using normalphase silica gel chromatography eluting with 15-70% EtOAc/Hexanes. Theproduct fractions were concentrated to yield2-chloro-3-(1-trityl-1H-pyrazol-4-yl)pyridine as an off-white solid. MSm/z=422 [M+1]⁺. Calc'd for C₂₇H₂₀ClN₃: 421.92.

Step 3. Preparation of4-(3-(1-trityl-1H-pyrazol-4-yl)pyridin-2-yloxy)benzenamine

In 4 separate microwave vessels were added equal amounts of thefollowing (total/4): dissolved 4-aminophenol (0.054 g, 0.498 mmol) in1-methyl-2-pyrrolidinone (4.7 mL), added cesium carbonate (0.309 g,0.948 mmol). Each mixture was stirred at 20° C. for 5 minutes, afterwhich was added 2-chloro-3-(1-trityl-1H-pyrazol-4-yl)pyridine (0.200 g,0.474 mmol) and heated to 200° C. in the microwave for 6 minutes. Thesolutions were combined and extracted into EtOAc, washed 1×H₂O, 1×NaCl,dried with Mg₂SO₄, filtered through fritted funnel, and concentrated.The crude residue was purified by silica gel chromatography using 25-70%EtOAc/Hexanes. The product fraction were concentrated to yield4-(3-(1-trityl-1H-pyrazol-4-yl)pyridin-2-yloxy)benzenamine as brown oil.MS m/z=495 [M+1]⁺. Calc'd for C₃₃H₂₆N₄O: 494.59.

Step 4. Preparation of 4-(3-(1H-pyrazol-4-yl)pyridin-2-yloxy)benzenamine

In a 25 mL sealed tube, was added4-(3-(1-trityl-1H-pyrazol-4-yl)pyridin-2-yloxy)benzenamine (0.150 g,0.303 mmol), trifluoroacetic acid (0.23 mL, 3.0 mmol), and methanol (1.0mL). The mixture was stirred at 80° C. for 36 hours. The mixture wasconcentrated. The residue was extracted into EtOAc, washed 1×NaHCO₃,1×NaCl, and the organic layers were combined and dried over Mg₂SO₄,filtered through fitted funnel and concentrated to yield4-(3-(1H-pyrazol-4-yl)pyridin-2-yloxy)benzenamine as dark brown waxysolid. MS m/z=253 [M+1]⁺. Calc'd for C₁₄H₁₂N₄O: 252.27.

Example 33

Synthesis of tert-butyl4-(2-(4-aminophenoxy)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylateStep 1. Preparation of tert-Butyl4-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (3.00 g, 19.7 mmol),N,N-dimethylpyridin-4-amine (1.20 g, 9.83 mmol), dichloromethane (67.8mL) was added di-tert-butyl dicarbonate (4.72 g, 21.6 mmol). Theresulting mixture was stirred at RT under nitrogen. After 18 h, LC-MSshowed only product (m/z=527, [M+Na]⁺). The reaction mixture was dilutedwith CH₂Cl₂, washed with saturated sodium bicarbonate, and washed withbrine. The organic phase was dried over magnesium sulfate, filtered, andconcentrated. The crude was purified using an ISCO column chromatographyon silica gel eluting with 90:10 Hex:EtOAc. The product fractions werecollected, concentrated and the oil was placed in the vacuum ovenovernight to removed EtOAc. White solids, tert-butyl4-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate were formed slowlyunder vacuum. MS m/z=527 [Dimer+Na]⁺. Calcd for C₁₂H₁₃ClN₂O₂: 252.07.

Step 2. Preparation of 4-(3-Bromopyridin-2-yloxy)benzenamine

3-Bromo-2-chloropyridine (10.3 g, 53.4 mmol), 4-aminophenol (7.00 g,64.1 mmol), cesium carbonate (34.8 g, 107 mmol), and DMSO (53 ml, 53.4mmol) were added into a sealed tube. The tube was capped and placed in apreheated oil bath at 130° C. After 16 h, LC-MS showed mainly product.While the reaction mixture was stirring and cooling in ice-water, waterwas added to induce the product to precipitate out of the solution. Agray solid was obtained, washed with water, dried under vacuum at rt. MSm/z=265 [M+1]⁺. Calcd for C₁₁H₉BrN₂O: 263.99.

Step 3. Preparation of4-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)benzenamine

Into a sealed tube was added 4-(3-bromopyridin-2-yloxy)benzenamine (5.38g, 20.0 mmol), 1,4-dioxane (101 ml, 20.0 mmol), and potassium acetate(6.00 g, 61.0 mmol). The tube was purged with argon. Then PdCl₂(DPPF)(0.700 g, 1.00 mmol) and4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(13.0 g, 53.0 mmol) were added. The reaction mixture was stirred for 0.5h at RT until a deep brown solution was formed. The reaction tube wasthen placed in a preheated oil bath at 85° C. After 18 h, LC-MSconfirmed that the reaction was completed. The reaction was cooled to RTand passed through a pad of celite eluting with the EtOAc, to remove theblack impurities. The filtrate was concentrated to give a brown oil,which was placed under vacuum over the weekend. The oil became solidproduct4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)benzenamine.MS m/z=313 [M+1]⁺. Calcd for C₁₇H₂₁BN₂O₃: 312.16.

Step 4. Preparation of tert-Butyl4-(2-(4-aminophenoxy)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

In an argon-purged sealed tube, tert-butyl4-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (2.77 g, 11.0 mmol),4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)benzenamine(5.14 g, 16.5 mmol), sodium carbonate (3.49 g, 32.9 mmol), 1,4-dioxane(32.3 mL), water (11.7 mL) were added. The reaction was stirred at rtfor 5 min. Then palladium acetate (0.246 g, 1.10 mmol) andtri-t-butylphosphonium tetrafluororoborate (0.637 g, 2.19 mmol) wereadded. The tube was sealed and heated to 100° C. After 1 h 45 min, thereaction was monitored and found to be complete. The reaction mixturewas cooled to rt and passed through a pad of celite, washing with EtOAc.The filtrate was dried over MgSO₄, filtered, and concentrated. The crudeproduct was purified by column chromatography on 120 g silica gel columnusing DCM and 95:05 DCM:(90:10:1 DCM:MeOH:NH₄OH) to flush out thenonpolar spots, then 80:20 DCM:(90:10:1 DCM:MeOH:NH₄OH) to collect theBoc-product. A viscous brown oil was obtained. After setting the oil atrt for several hours, small amounts of crystalline colonies were formed.The oil was cooled to 0° C. and light yellow solid precipitated outafter adding small amounts of hexanes and a little bit of ether inaddition to scratching the wall of the flash with a spatula. The lightyellow solid was filtered, washed with cold hexanes, and dried undervacuum. This solid, tert-butyl4-(2-(4-aminophenoxy)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylatewas obtained. MS m/z=403 [M+1]⁺. Calcd for C₂₃H₂₂N₄O₃: 402.17.

Example 34

Synthesis of4-(2-(5-Aminopyridin-2-yloxy)pyridin-3-yl)-N-methylpyridin-2-amine

In a microwave vial, 5-aminopyridin-2-ol (125 mg, 1.14 mmol) wasdissolved in DMSO (0.910 mL, 0.228 mmol) and cesium carbonate (445 mg,1.37 mmol) was added. The vial was capped with a septum and the reactionwas stirred at RT for 25 minutes until a paste was formed. Then4-(2-chloropyridin-3-yl)-N-methylpyridin-2-amine (50 mg, 0.23 mmol) wasadded and the vial was sealed and heated to 180° C. in PersonalChemistry Microwave for 15 min. The mixture was extracted with EtOAc,organic layers were washed with brine, dried over MgSO₄, filtered, andconcentrated. The product was purified by column chromatography onsilica gel using 60:40 DCM:(90:10:1 DCM:MeOH:NH₄OH to flush out topspots, then 50:50 DCM:(90:10:1 DCM:MeOH:NH₄OH) to collect the product.Green solid,4-(2-(5-aminopyridin-2-yloxy)pyridin-3-yl)-N-methylpyridin-2-amine wasobtained. MS m/z=294 [M+1]⁺. Calcd for C₁₆H₁₅N₅O: 293.13.

Example 35

Synthesis of tert-butyl4-(2-(4-aminophenoxy)pyridin-3-yl)picolinoyl(methyl)carbamate Step 1.Preparation of tert-Butyl 4-chloropicolinoyl(methyl)carbamate

The title compound was made following the procedure disclosed in thefollowing references: (a) Marino, J. P.; Rubio, M. B.; Cao, G.; de Dios,A. J. Am. Chem. Soc. 2002, 124, 13398. (b) Diaz, D. D.; Finn, M. G. Org.Lett. 2004, 6, 43. (c) Padwa, A.; Brodney, M. A.; Lynch, S. M.;Rashatasakhon, P.; Wang, Q.; Zhang, H. J. Org. Chem. 2004, 69, 3735). Asdescribed, a solution of 4-chloro-N-methylpicolinamide (1.00 g, 5.86mmol) in THF (11.7 ml, 5.86 mmol) was cooled to −78° C. Then n-BuLi(2.36 mL, 5.86 mmol) in THF was added dropwise at −78° C. The resultingthick yellow suspension was stirred at −78° C. for 30 min, then warmedto 0° C., stirred at this temperature for 10 min, and cooled back downto −78° C. Di-tert-butyl dicarbonate (2.30 mg, 10.6 mmol) in 5 mL of THFwas added dropwise. The reaction was stirred at −78° C. for 0.5 h and at0° C. for 20 min, and warmed to RT for 10 min. After 2 days, LC-MSshowed 1:1 Prod:SM. The reaction extracted with EtOAc, and the organiclayers were washed with brine, dried over MgSO₄, filtered, andconcentrated. The product was purified by column chromatography usingsilica gel eluting with 80:20 Hex:EtOAc. Tert-butyl4-chloropicolinoyl(methyl)carbamate was collected as light yellow solid.MS m/z=563 [Dimer+Na]⁺. Calcd for C₁₂H₁₅ClN₂O₃: 270.08.

Step 2. Preparation of tert-Butyl4-(2-(4-aminophenoxy)pyridin-3-yl)picolinoyl(methyl)carbamate

In an argon-purged sealed tube, tert-butyl4-chloropicolinoyl(methyl)carbamate (50 mg, 0.19 mmol),4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)benzenamine(173 mg, 0.554 mmol), sodium carbonate (59 mg, 0.55 mmol), palladiumacetate (4.0 mg, 0.018 mmol), and tri-t-butylphosphoniumtetrafluororoborate (11 mg, 0.037 mmol) were added followed by1,4-dioxane (0.543 mL, 0.185 mmol) and water (0.196 mL, 0.185 mmol). Themixture was stirred at rt for 5 min, then the tube was sealed and placedin a preheated oil bath at 100° C. After 2.5 h, the product wasextracted with EtOAc, washed with brine, dried over MgSO₄ andconcentrated. The crude product was purified by silica gelchromatography on an ISCO column eluting with 80:20 DCM:(90:10:1DCM:MeOH:NH₄OH). A brown oil was obtained which was mainly product,tert-butyl4-(2-(4-aminophenoxy)pyridin-3-yl)picolinoyl(methyl)carbamate. MSm/z=421 [M+1]⁺. Calcd for C₂₃H₂₄N₄O₄: 420.18.

Example 36

Synthesis of 4-(2-(4-aminophenoxy)pyridin-3-yl)picolinonitrile

In an argon-purged sealed tube, 4-bromopicolinonitrile (500 mg, 2.73mmol),4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)benzenamine(2.56 g, 8.20 mmol), sodium carbonate (869 mg, 8.20 mmol), palladiumacetate (61 mg, 273 μmol), and tri-t-butylphosphoniumtetrafluororoborate (159 mg, 546 μmol) were added followed by1,4-dioxane (8.04 ml, 2.73 mmol) and water (2.90 ml, 2.73 mmol). Thereaction was stirred at RT for 5 min. The tube was sealed and placed ina preheated oil bath at 100° C. After 2 h, LC-MS showed product at 1.321min. The product was extracted with EtOAc, washed with brine, dried overMgSO₄ and concentrated. The title compound was purified by silica gelchromatography on an ISCO column eluting with 80:20 DCM:(90:10:1DCM:MeOH:NH₄OH), to obtain an off white solid. MS m/z=289 [M+1]⁺. Calcdfor C₁₇H₁₂N₄O: 288.10.

Example 37

Synthesis of 4-(2-(4-aminophenoxy)pyridin-3-yl)picolinamide. The titlecompound was prepared according to the reference: Katritzky, A. R.;Pilarski, B.; Urogdi, L. Synthesis 1989, 949. As described, a solutionof 4-(2-(4-aminophenoxy)pyridin-3-yl)picolinonitrile (764 mg, 2.65 mmol)in DMSO (0.883 mL, 2.65 mmol) was cooled to 0° C. 2.7 mL of 30% Hydrogenperoxide in water was added followed by potassium carbonate (37 mg, 0.27mmol). The solution became a thick, milky white suspension. The mixturewas warmed to rt. After 10 min, 1 mL of H₂O₂ and 20 mg of K₂CO₃ wereadded. After 20 min, LC-MS showed that the reaction was completed. Thewhite solid was filtered off and washed with water. The product wasdried under vacuum, to afford4-(2-(4-aminophenoxy)pyridin-3-yl)picolinamide. MS m/z=307 [M+1]⁺. Calcdfor C₁₇H₁₄N4O₂: 306.11.

Example 38

Synthesis of 5-(2-(4-aminophenoxy)pyridin-3-yl)thiazol-2-amine

In a 20 mL sealed tube was added dioxane (1.0 mL), purged solvent withnitrogen for 5 minutes and the tube was sealed.4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)benzenamine(0.144 g, 0.462 mmol), 5-bromothiazol-2-amine hydrobromide (0.100 g,0.385 mmol), 2.0M aqueous sodium carbonate (0.385 mL) was added and thetube was purged flask with nitrogen, and again sealed.Tris(dibenzylideneacetone)dipalladium (0) (0.026 g, 0.029 mmol),tri-t-butylphosphonium tetrafluoroborate (0.025 g, 0.087 mmol) was addedand the tube was purged with nitrogen, sealed and heated to 100° C.while stirring for 5 hours. The mixture was cooled to RT, passed throughpad of silica, washing with 90:10:1 (CH₂Cl₂: MeOH: NH₄OH). The eluentwas concentrated and the product was purified by silica gelchromatography eluting with 0-100% CH₂Cl₂:MeOH(90:10)/CH₂Cl₂. Theproduct fractions were concentrated to yield5-(2-(4-aminophenoxy)pyridin-3-yl)thiazol-2-amine as tan solid. MSm/z=285 [M+1]⁺. Calc'd for C₁₄H₁₂N₄OS: 284.34.

Example 39

Synthesis of 4-(2-(4-aminophenoxy)pyridin-3-yl)-5-methylisoxazol-3-amine

In a 20 mL sealed tube was added dioxane (1.0 mL), which was purged withnitrogen for 5 minutes and the tube sealed. To this was added3-amino-4-bromo-5-methylisoxazole (0.100 g, 0.565 mmol),4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)benzenamine(0.265 g, 0.847 mmol), 2.0M aqueous sodium carbonate (0.565 mL, 1.13mmol) and the tube was purged with nitrogen and sealed. To the mixturewas added tri-t-butylphosphonium tetrafluoroborate (0.037 g, 0.13 mmol),tris(dibenzylideneacetone)dipalladium (0) (0.039 g, 0.042 mmol) and thetube was purged with nitrogen, sealed and heated to 100° C. withstirring for 5 hours. The mixture was cooled to RT, passed through padof silica, which was washed with 100% CH₂Cl₂:MeOH:NH₄OH(90:10:1)/CH₂Cl₂. The eluent was concentrated and purified on a Gilsonreverse phase chromatography system. The product fractions wereextracted into CH₂Cl₂, washed 1× saturated NaHCO₃, 1×H₂O, dried withNa₂SO₄, filtered through fritted funnel and concentrated to yield4-(2-(4-aminophenoxy)pyridin-3-yl)-5-methylisoxazol-3-amine as lightyellow solid. MS m/z=283 [M+1]⁺. Calc'd for C₁₅H₁₄N₄O₂: 282.30.

The following intermediates and compounds were made using intermediatesmade by methods described in the examples above.

Example 40

Synthesis of4-chloro-5,8-difluoro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine

To 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.100g, 0.34 mmol) and 1,4-dichloro-5,8-difluorophthalazine (0.096 g, 0.41mmol) was added tBuOH (1.0 mL). The resulting mixture was heated to 100°C. in a sealed tube for 45 min. The reaction was diluted with diethylether and the resulting solids were filtered and triturated with EtOAc.The solids were dried to yield4-chloro-5,8-difluoro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amineas a dark gray solid. MS m/z=492 [M+H]⁺. Calc'd for C₂₄H₁₆ClF₂N₇O:491.89.

Example 41

Synthesis of4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-5,6,7,8-tetrahydrophthalazin-1-amine

A slurry of 1,4-dichloro-5,6,7,8-tetrahydrophthalazine (1.66 g, 8.18mmol) and 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine(2.00 g, 6.82 mmol) in 14 mL 2-BuOH was heated in a sealed pressurevessel to 110° C. The reaction became a thick mass that eventuallybecame a stirring suspension over about 30 min. After 4 h, the reactionwas cooled to ambient temperature, and the material was partitionedbetween 2N NaOH and EtOAc. The aqueous layer was extracted once withEtOAc. The organic layers were dried over anhyd. sodium sulfate,filtered, and concentrated to yield a brown solid. This solid wasdissolved in MeOH/MC and adsorbed onto 10 g silica gel, dried, andpurified by chromatography (0-100% EtOAc/DCM) to give4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-5,6,7,8-tetrahydrophthalazin-1-amineas an off-white solid. MS m/z=460 [M+H]⁺. Calc'd for C₂₄H₂₂ClN₇O: 459.9.

Example 41-A

Synthesis of4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-5,6,7,8-tetrahydrophthalazin-1-amine

A resealable reaction tube was charged with1,4-dichloro-5,6,7,8-tetrahydrophthalazine (0.050 g, 0.246 mmol),4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.072 g,0.246 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.011 g, 0.012mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.020 g,0.049 mmol), and sodium tert-butoxide (0.033 g, 0.345 mmol). The vialwas purged with nitrogen for several minutes, followed by addition of0.50 mL of toluene. The vial was capped and heated to 150° C. for 16 h.The reaction mixture was allowed to cool and was filtered through a plugof Celite, rinsing with dichloromethane. The filtrate was concentrated,and the crude material was purified by reverse phase chromatography,Gilson, 5-95% acetonitrile/H₂O/0.1% TFA over 14 min. Theproduct-containing fractions were combined, brought to basic pH byaddition of 2M Na₂CO₃ and extracted with dichloromethane. The organicportion was dried with MgSO₄, filtered, and concentrated to give4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-5,6,7,8-tetrahydrophthalazin-1-amineas a light brown solid. MS m/z=460 [M+H]⁺. Calc'd for C₂₄H₂₂ClN₇O:459.93.

Example Method A1

Synthesis ofN-(4-(3-(2-(methylamino)pyridin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine

To 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyridin-2-amine (0.070 g,0.24 mmol) and 1-chloro-4-phenylphthalazine (0.048 g, 0.20 mmol) wasadded tBuOH (1.0 mL). The resulting mixture was heated at 100° C. in asealed tube for 16 hours. The reaction was diluted with diethyl etherand saturated sodium carbonate and vigorously shaken. The resultingsolids were filtered and washed with water, diethyl ether and air driedto yieldN-(4-(3-(2-(methylamino)pyridin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amineas an off-white solid. MS m/z=497 [M+H]⁺. Calc'd for C₃₁H₂₄N₆O: 496.58.

Example Method A2

Synthesis ofN-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine

A slurry of 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine (0.15 g,0.54 mmol), 1-chloro-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyridazine(0.113 g, 0.49 mmol), 2,2,2-trifluoroacetic acid (0.11 ml, 1.5 mmol) in2 mL 2-BuOH was heated in a sealed tube to 110° C. The reaction became athick orange mixture. After 2-3 h, the reaction was cooled, andpartitioned between EtOAc and 2N NaOH. The organic layer was dried overanhyd. sodium sulfate, filtered, and concentrated. The solid wasadsorbed onto silica gel from MeOH/DCM, and dried, and purified bysilica gel chromatography (0-80% 90/10 DCM/MeOH in DCM to give 80 mg ofimpure material. This was further purified by reverse-phase HPLC,(ACN/H2O+0.1% TFA) to giveN-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amineas a white solid. MS m/z=474 [M+H]⁺. Calc'd for C₂₈H₂₃N₇O: 473.5.

Example Method A3

Synthesis ofN-(4-(3-(2-(methylamino)pyridin-4-yl)pyridin-2-yloxy)phenyl)-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine

A resealable reaction tube was charged withtris(dibenzylideneacetone)dipalladium (0) (0.012 g, 0.013 mmol),2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.021 g, 0.051mmol), 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyridin-2-amine (0.075g, 0.257 mmol), 1-chloro-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyridazine(0.059 g, 0.257 mmol), and sodium tert-butoxide (0.035 g, 0.359 mmol).This mixture was purged with nitrogen for several minutes, followed byaddition of 0.780 mL of toluene. The vial was capped and heated at 100°C. for 1.5 h. Upon cooling, ethyl acetate was added and a precipitateformed. After filtration and washing with EtOAc, the crude material waspurified by ISCO silica gel chromatography (90/10/1 DCM/MeOH/NH₄OH, 12 gcolumn), to provideN-(4-(3-(2-(methylamino)pyridin-4-yl)pyridin-2-yloxy)phenyl)-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amineas a tan solid. MS m/z=487 [M+H]⁺. Calc'd for C₃₀H₂₆N₆O: 486.57.

Example Method B1

Synthesis of5,8-difluoro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine

To phenylboronic acid (0.030 g, 0.24 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.0060 g,0.0081 mmol) and4-chloro-5,8-difluoro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine(0.080 g, 0.16 mmol) was added dioxane (0.35 mL) and sodium carbonate(2.0 M, aqueous) (0.16 ml, 0.33 mmol). The resulting mixture was heatedto 85° C. in a sealed tube for 60 minutes. The reaction was diluted withEtOAc and water, and the layers were separated and the organic layerswere dried over sodium sulfate, filtered and concentrated. The crude waspurified by ISCO silica gel chromatography (20-100% EtOAc/hexanes; 40 gcolumn). Concentrated product fractions to yield5,8-difluoro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amineas an off-white solid. MS m/z=534 [M+H]⁺. Calc'd for C₃₀H₂₁F₂N₇O:533.54.

Example Method B2

Synthesis ofN-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(thiazol-2-yl)phthalazin-1-amine

A resealable pressure tube, purged with argon, was charged with4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine(150 mg, 0.329 mmol), tetrakis(triphenylphosphine)palladium (38 mg,0.033 mmol), and 2-(tributylstannyl)thiazole (0.207 mL, 0.658 mmol).This mixture was purged with argon for 10 minutes, followed by additionof toluene (1.6 ml, 0.2 M). Tube was sealed and mixture heated to 110°C. overnight. Next day LC/MS shows completion of reaction. The reactionwas stopped, cooled to RT and concentrated under reduced pressure to abrown residue. This residue was purified by Gilson reverse phasechromatography (10% to 90% CH₃CN/H₂O/0.1% TFA). The product-containingfractions were combined, basified by addition of aq. NaHCO₃ andextracted with ethyl acetate. The organic portion was dried with Na₂SO₄,filtered, and concentrated to afford pureN-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(thiazol-2-yl)phthalazin-1-amineas a yellow solid. MS m/z=505 [M+H]⁺. Calc'd for C₂₇H₂₀N₈OS: 504.57.

Example Method B3

Synthesis of4-(3,3-dimethylbut-1-ynyl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine

A resealable pressure tube, purged with argon, was charged with4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine(150 mg, 0.329 mmol), bis(triphenylphosphine)palladium(II) chloride (14mg, 0.020 mmol), copper(I) iodide (3.8 mg, 0.020 mmol), and3,3-dimethyl-1-butyne (0.101 mL, 0.823 mmol). This mixture was purgedwith argon for 10 minutes, followed by addition of acetonitrile (3.3 ml,0.1 M). The pressure tube was sealed and the mixture inside heated to90° C. for 16 hrs. The next day, the reaction was stopped, cooled to RT,diluted with dichloromethane and filtered over a plug of celite.Filtrate was concentrated to afford a brown residue, which was purifiedby Gilson reverse phase chromatography (10% to 90% CH₃CN/H₂O/0.1% TFA).The product-containing fractions were combined, basified by addition ofaq. NaHCO₃ and extracted with ethyl acetate. The organic portion wasdried with Na₂SO₄, filtered, and concentrated to afford pure4-(3,3-dimethylbut-1-ynyl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amineas a yellow solid. MS m/z=502 [M+H]⁺. Calc'd for C₃₀H₂₇N₇O: 501.58.

Example Method B4

Synthesis ofN-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-morpholinophthalazin-1-amine

To a resealable tube was added4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine(120 mg, 0.263 mmol) and DMSO (0.526 mL, 0.5 M). To this solution wasadded morpholine (0.689 mL, 7.89 mmol) and TEA (0.037 mL, 0.26 mmol),and the reaction mixture was heated at 100° C. for 48 h. The reactionwas cooled and concentrated under reduced pressure. The crude residuewas dissolved in dichloromethane and purified by Biotage columnchromatography on silica gel (1%-5% MeOH/Dichloromethane); whichprovided pureN-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-morpholinophthalazin-1-amineas a yellow solid. MS m/z=507 [M+H]⁺. Calc'd for C₂₈H₂₆N₈O₂: 506.56.

Example Method B5

Synthesis ofN-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(piperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine

To a mixture of4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine(0.200 g, 0.449 mmol) and piperidine (0.310 ml, 3.14 mmol) in 2 mL2-butanol was added TFA (0.173 ml, 2.24 mmol). The reaction becameslightly homogeneous and then solid. The solid was heated to 125° C. for24 h, showing a small amount of conversion. The reaction was heated to135° C. for 3 days. The brown, homogeneous reaction was allowed to cool,and was diluted with 2N NaOH, water, and EtOAc. The organic layer wasdried over anhydrous sodium sulfate, filtered, and concentrated. Theresulting solid was adsorbed onto 2 g silica gel and purified bychromatography (0-100% 90/10 DCM/MeOH in DCM) to giveN-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(piperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amineas an off-white solid. MS m/z=495 [M+H]⁺. Calc'd for C₂₈H₃₀N₈O: 494.6.

Example Method B6

Synthesis ofN-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiazol-2-yl)phthalazin-1-amine

A dry 25 ml round bottom flask under nitrogen was charged with 2.5 MnBuLi in Hexanes (0.420 ml, 1.06 mmol); which was diluted with THF (1ml). This was cooled to −78° C. and 4-methylthiazole (100 mg, 1.01 mmol)dissolved in 2 ml of THF was added slowly via syringe. This was stirredat −78° C. for 2 hours, slowly warmed up to −10° C. and stirred at thistemperature for 0.5 hour. Reaction cooled back to −78° C. and 0.5Mzinc(II) chloride in THF (3.03 ml, 1.51 mmol) added via syringe.Reaction stirred at −78° C. for 0.5 hour then at room temperature for 1hour. At this time,4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine(115 mg, 0.250 mmol) and Pd(PPh₃)₄ (58 mg, 0.05 mmol) added and reactionstirred under nitrogen at 65° C. for 48 hours. Reaction stopped, cooledto room temperature, diluted with aq. EDTA/NaHCO₃ solution. This wasextracted with ethyl acetate. Organic portion was dried with Na₂SO₄,filtered, and concentrated to give light brown residue. This waspurified by Gilson reverse phase chromatography (10% to 90%CH₃CN/H₂O/0.1% TFA). The product-containing fractions were combined,basified by addition of Aq. NaHCO₃ and extracted with ethyl acetate. Theorganic portion was dried with Na₂SO₄, filtered, concentrated to affordpureN-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiazol-2-yl)phthalazin-1-amineas a yellow solid. MS m/z=519 [M+H]⁺. Calc'd for C₂₈H₂₂N₈OS: 518.59.

Example Method B7

Synthesis of4-(4-methyl-1H-pyrazol-1-yl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine

A dry resealable pressure bottle, under nitrogen, was charged with4-methylpyrazole (0.086 ml, 1.05 mmol). To this was added THF (1.3 ml,0.2 M) and reaction mixture cooled to 0° C. 60% wt sodium hydride inmineral oil (44.0 mg, 1.10 mmol) was added slowly. Reaction mixturestirred at 0° C. for 15 minutes and4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine(120 mg, 0.260 mmol) added slowly. Reaction kept at 0° C. for 10minutes, then warmed up slowly to room temperature and placed in an oilbath. Reaction heated to 65° C. and stirred at this temperatureovernight. Reaction mixture was cooled to 0° C. and diluted with water,and extracted with EtOAc. The organic layer was collected, dried overNa₂SO₄ and concentrated to afford an orange residue, which was purifiedby Gilson reverse phase chromatography (10% to 90% CH₃CN/H₂O/0.1% TFA).The product-containing fractions were combined, basified by addition ofaq. NaHCO₃ and extracted with ethyl acetate. The organic portion wasdried with Na₂SO₄, filtered, and concentrated to afford pure4-(4-methyl-1H-pyrazol-1-yl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amineas a yellow solid. MS m/z=502 [M+H]⁺. Calc'd for C₂₈H₂₃N₉O: 501.54.

Example Method C

Synthesis ofN-methyl-4-(2-(4-((4-phenylphthalazin-1-yl)methyl)phenoxy)pyridin-3-yl)pyrimidin-2-amine

To a mixture of 4-(2-chloropyridin-3-yl)-N-methylpyrimidin-2-amine(0.0500 g, 0.23 mmol), 4-((4-phenylphthalazin-1-yl)methyl)phenol (0.071g, 0.23 mmol) and cesium carbonate (0.15 g, 0.45 mmol) was added DMSO(0.5 mL). The resulting mixture was heated to 130° C. in a sealed tubefor 15 hours, then diluted with EtOAc and extracted with saturatedsodium bicarbonate. The organic layer was dried over sodium sulfate,filtered and concentrated. The crude concentrate was purified by Gilsonreverse-phase HPLC (0.1% TFA in ACN/water; 15-95% ACN; 40 mL/min).Diluted product with DCM and extracted with saturated sodiumbicarbonate. Dried organics over sodium sulfate, filtered andconcentrated. Lyophilized concentrate to obtainedN-methyl-4-(2-(4-((4-phenylphthalazin-1-yl)methyl)phenoxy)pyridin-3-yl)pyrimidin-2-amineas a white solid. MS m/z=497 [M+H]⁺. Calc'd for C₃₁H₂₄N₆O: 496.58.

Example Method D

Synthesis ofN-(4-(3-(2-(3-(dimethylamino)-2,2-dimethylpropylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amineStep 1. Preparation of4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)benzenamine

A resealable pressure bottle was charged with4-(2-chloropyridin-3-yl)-2-(methylthio)pyrimidine (6.00 g, 25.2 mmol),4-aminophenol (2.89 g, 26.5 mmol), and cesium carbonate (16.4 g, 50.5mmol). These reagents were suspended in DMSO (50.5 ml, 0.50 M). Thevessel was sealed and heated to 130° C. for 48 hrs. Reaction mixture wasallowed to cool to RT, diluted with water and extracted with EtOAc. Theorganic layer was collected, dried with Na₂SO₄, filtered, andconcentrated to give a light brown residue, which was purified by silicagel chromatography (ISCO, 10% to 50% Ethyl Acetate/Hexanes) to affordclean material as light yellow solid. MS m/z=311 [M+H]⁺. Calc'd forC₁₆H₁₄N₄OS: 310.37.

Step 2. Preparation ofN-(4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine

A resealable pressure bottle was charged with4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)benzenamine (1.78 g,5.74 mmol), 1-chloro-4-phenylphthalazine (1.38 g, 5.74 mmol) andsuspended in butan-2-ol (28.7 ml, 0.20 M) under nitrogen. The vessel wassealed and heated to 100° C. for 6 hrs. The reaction mixture was allowedto cool to RT, upon which a precipitate formed. The precipitate wasfiltered and washed with dichloromethane, collected and dried under highvacuum to provide the HCl salt ofN-(4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amineas a light yellow solid. MS m/z=515 [M+H]⁺. Calc'd for C₃₀H₂₂N₆OS:514.60.

Step 3. Preparation ofN-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine

A 100 ml dried round bottom flask was charged withN-(4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-aminehydrochloride (1.25 g, 2.27 mmol) and sonicated in methanol (20.6 ml,0.11 M) for 20 minutes. To this was added oxone (4.18 g, 6.81 mmol) andthe mixture was stirred at RT for 2 days. The mixture was cooled to 0°C. and basified with aq. NaHCO₃. The solids were filtered, washed withwater, and dried under high vacuum to provideN-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amineas a light yellow solid. MS m/z=547 [M+H]⁺. Calc'd for C₃₀H₂₂N₆O₃S:546.60.

Step 4. Preparation ofN-(4-(3-(2-(3-(dimethylamino)-2,2-dimethylpropylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine

A resealable pressure vial was charged withN-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine(100 mg, 0.180 mmol) and N1,N1,2,2-tetramethylpropane-1,3-diamine (0.12ml, 0.73 mmol) and DMSO (1.2 ml, 0.15 M). The reaction vessel was sealedand the mixture was stirred at 70° C. for 16 hrs. The reaction wascooled to RT and diluted with 3 ml of DMSO. The solution was purified byGilson reverse phase chromatography (10% to 90% CH₃CN/H₂O/0.1% TFA). Theproduct-containing fractions were combined, basified by addition of aq.NaHCO₃ and extracted with ethyl acetate. The organic portion was driedwith Na₂SO₄, filtered, and concentrated to afford pureN-(4-(3-(2-(3-(dimethylamino)-2,2-dimethylpropylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amineas a yellow solid. MS m/z=597 [M+H]⁺. Calc'd for C36H36N8O: 596.72.

The following compounds (Examples 42-240) in Table I were made, as notedin table I, by one of the exemplified methods A1, A2, A3, B1, B2, B3,B4, B5, B6, B7, C or D described above. The MS data represent the mass(M+H⁺) found for that example.

TABLE 1 Ex. MS No. Name Formula Data Method 42N-methyl-N-(4-((3-(2-(methylamino)-4- C₃₁H₂₅N₇O 512 A1pyrimidinyl)-2-pyridinyl)oxy) phenyl)-4-phenyl-1- phthalazinamine 43N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₉H₂₂N₈O 499 A1pyridinyl)oxy) phenyl)-4-(2-pyridinyl)-1- phthalazinamine 44N-(6-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)- C₂₇H₁₉N₉O 486 A13-pyridinyl)-4-(2-pyridinyl)-1-phthalazinamine 45N-(4-(3,4′-bipyridin-2-yloxy)phenyl)-4-phenyl-1- C₃₀H₂₁N₅O 468 A1phthalazinamine 46 N-(3-methyl-4-((3-(2-(methylamino)-4- C₂₆H₂₂N₆O 435A1 pyrimidinyl)-2-pyridinyl)oxy) phenyl)-1- isoquinolinamine 47N-(3-methyl-4-((3-(2-(methylamino)-4- C₂₆H₂₂N₆O 435 A1pyrimidinyl)-2-pyridinyl)oxy) phenyl)-2- quinolinamine 484-(3,5-dimethyl-1H-pyrazol-1-yl)-N-(4-((3-(2- C₂₉H₂₅N₉O 516 A1(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy) phenyl)-1-phthalazinamine49 N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₈H₂₁N₇OS 504 A1pyridinyl)oxy) phenyl)-4-(2-thienyl)-1- phthalazinamine 504-phenyl-N-(4-((3-(4-pyrimidinyl)-2- C₂₉H₂₀N₆O 469 A1pyridinyl)oxy)phenyl)-1-phthalazinamine 51N-(4-((3-(5-fluoro-2-(methylamino)-4- C₂₉H₂₇FN₈O 523 A1pyrimidinyl)-2-pyridinyl)oxy) phenyl)-4-(1-piperidinyl)-1-phthalazinamine 52 2-((4-((4-(4-fluorophenyl)-1-C₃₁H₂₃FN₆O 515 A1 phthalazinyl)amino)phenyl)oxy)-N-methyl-3,4′-bipyridin-2′-amine 53 4-(4-fluorophenyl)-N-(4-((3-(1H-pyrrolo[2,3-C₃₂H₂₁FN₆O 525 A1 b]pyridin-4-yl)-2-pyridinyl)oxy)phenyl)-1-phthalazinamine 54 4-(4-fluorophenyl)-N-(4-((3-(1H-pyrazolo[3,4-C₃₁H₂₀FN₇O 526 A1 b]pyridin-4-yl)-2-pyridinyl)oxy)phenyl)-1-phthalazinamine 55 N-(4-((3-(1H-pyrazolo[3,4-b]pyridin-4-yl)-2-C₂₉H₁₉N₇OS 514 A1 pyridinyl)oxy)phenyl)-4-(2-thienyl)-1- phthalazinamine56 4-phenyl-N-(4-((3-(1H-pyrazolo[3,4-b]pyridin-4- C₃₁H₂₁N₇O 508 A1yl)-2-pyridinyl)oxy) phenyl)-1-phthalazinamine 574-(4-methyl-2-thienyl)-N-(4-((3-(1H-pyrazolo[3,4- C₃₀H₂₁N₇OS 528 A1b]pyridin-4-yl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 584-(1-piperidinyl)-N-(4-((3-(1H-pyrazolo[3,4- C₃₀H₂₆N₈O 515 A1b]pyridin-4-yl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 59N-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2- C₂₇H₁₉N₇OS 490 A1yloxy)phenyl)-4-phenylthieno[3,2-d]pyridazin-7- amine 602-((5-((4-(4-fluorophenyl)-1-phthalazinyl)amino)-2- C₃₀H₂₂FN₇O 516 A1pyridinyl) oxy)-N-methyl-3,4′-bipyridin-2′-amine 614-phenyl-N-(4-((3-(1H-pyrrolo[2,3-b]pyridin-4-yl)- C₃₂H₂₂N₆O 527 A12-pyridinyl)oxy) phenyl)-1-phthalazinamine 62N-(cyclopropylmethyl)-2-((4-((4-phenyl-1- C₃₄H₂₈N₆O 557 A1phthalazinyl)amino) phenyl)oxy)-3,4′-bipyridin-2′- amine 634-(4-methyl-2-thienyl)-N-(4-((3-(1H-pyrrolo[2,3- C₃₁H₂₂N₆OS 527 A1b]pyridin-4-yl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 644-(3-chlorophenyl)-N-(4-((3-(1H-pyrrolo[2,3- C₃₂H₂₁ClN₆O 541 A1b]pyridin-4-yl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 65N-methyl-2-((4-((4-phenyl-1- C₃₂H₂₄N₆O₂ 525 A1phthalazinyl)amino)phenyl)oxy)-3,4′-bipyridine-2′- carboxamide 664-(2-(4-(4-phenylphthalazin-1- C₃₁H₂₂N₆O₂ 511 A1ylamino)phenoxy)pyridin-3-yl) picolinamide 67N-(4-((3-(2-amino-4-pyrimidinyl)-2- C₂₈H₂₆N₈O 491 A1pyridinyl)oxy)phenyl)-4-(1-piperidinyl)-1- phthalazinamine 68N-(6-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₈H₂₇N₉O 506 A1pyridinyl)oxy)-3-pyridinyl)-4-(1-piperidinyl)-1- phthalazinamine 69N-methyl-2-((4-((4-(1-piperidinyl)-1- C₃₀H₂₉N₇O 504 A1phthalazinyl)amino)phenyl)oxy)-3,4′-bipyridin-2′- amine 70N-methyl-2-((4-((4-(4-methylphenyl)-1- C₃₂H₂₆N₆O 511 A1 phthalazinyl)amino)phenyl)oxy)-3,4′-bipyridin-2′- amine 71N-(3-fluoro-4-((3-(2-(methylamino)-4- C₂₉H₂₇FN₈O 523 A1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(1-piperidinyl)-1-phthalazinamine 72N-(6-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)- C₂₈H₁₉FN₈O 503 A13-pyridinyl)-4-(4-fluorophenyl)-1-phthalazinamine 73N-(6-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)- C₂₆H₁₈N₈OS 491 A13-pyridinyl)-4-(2-thienyl)-1-phthalazinamine 742-((2-fluoro-4-((4-(4-fluorophenyl)-1-phthalazinyl) C₃₁H₂₂F₂N₆O 533 A1amino)phenyl)oxy)-N-methyl-3,4′-bipyridin-2′- amine 75N-(4-((3-(4-(methylamino)-1,3,5-triazin-2-yl)-2- C₃₀H₂₄N₈O 513 A1pyridinyl) oxy) phenyl)-4-(4-methylphenyl)-1- phthalazinamine 76N-(4-((3-(2-amino-4-pyrimidinyl)-2- C₂₉H₂₀FN₇O 502 A1pyridinyl)oxy)phenyl)-4-(4-fluorophenyl)-1- phthalazinamine 774-(4-fluorophenyl)-N-(4-((3-(4-(methylamino)- C₂₉H₂₁FN₈O 517 A11,3,5-triazin-2-yl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 78N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)- C₂₉H₁₉F₂N₇O 520 A13-fluorophenyl)-4-(4-fluorophenyl)-1- phthalazinamine 79N-(4-((5-chloro-3-(2-(methylamino)-4- C₃₀H₂₁ClFN₇O 550 A1pyrimidinyl)-2-pyridinyl)oxy) phenyl)-4-(4-fluorophenyl)-1-phthalazinamine 80N-(4-((3-(4-(methylamino)-1,3,5-triazin-2-yl)-2- C₂₇H₂₀N₈OS 505 A1pyridinyl) oxy)phenyl)-4-(2-thienyl)-1- phthalazinamine 81N-(6-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)- C₂₈H₂₀N₈O 485 A13-pyridinyl)-4-phenyl-1-phthalazinamine 82N-(4-((3-(2-amino-4-pyrimidinyl)-2- C₂₉H₂₁N₇O 484 A1pyridinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine 834-(4-fluorophenyl)-N-(4-((3-(4-pyrimidinyl)-2- C₂₉H₁₉FN₆O 487 A1pyridinyl)oxy)phenyl)-1-phthalazinamine 844-(4-chlorophenyl)-N-(4-((3-(4-pyrimidinyl)-2- C₂₉H₁₉ClN₆O 503 A1pyridinyl)oxy)phenyl)-1-phthalazinamine 85N-(4-((3-(3-amino-5-methyl-4-isoxazolyl)-2- C₂₉H₂₂N₆O₂ 487 A1pyridinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine 86N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2- C₃₀H₂₃N₇S 514 A1ylthio)phenyl)-4-phenylphthalazin-1-amine 874-(3,4-dimethylphenyl)-N-(4-((3-(2-(methylamino)- C₃₂H₂₇N₇O 526 A14-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 88N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₉H₂₈N₈O 505 A1pyridinyl)oxy)phenyl)-4-(1-piperidinyl)-1- phthalazinamine 894-chloro-N-(4-((3-(2-(methylamino)-4- C₂₄H₁₈ClN₇O 456 A1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 90N-(4-((3-(2-amino-4-pyrimidinyl)-2- C₂₇H₁₉N₇OS 490 A1pyridinyl)oxy)phenyl)-4-(3-thienyl)-1- phthalazinamine 91N-methyl-2-((4-((4-(3-thienyl)-1- C₂₉H₂₂N₆OS 503 A1phthalazinyl)amino)phenyl)oxy)-3,4′-bipyridin-2′- amine 92N-(6-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₇H₂₀N₈OS 505 A1pyridinyl)oxy)-3-pyridinyl)-4-(3-thienyl)-1- phthalazinamine 93N-(4-((3-(4-pyrimidinyl)-2-pyridinyl) oxy)phenyl)- C₂₇H₁₈N₆OS 475 A14-(3-thienyl)-1-phthalazinamine 94 N-(3-fluoro-4-((3-(2-(methylamino)-4-C₃₀H₂₂FN₇O 516 A1 pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine 95 N-(4-((3-(2-amino-4-pyrimidinyl)-2- C₂₈H₂₁N₇OS 504 A1pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1- phthalazinamine 96N-(4-((3-(4-amino-1,3,5-triazin-2-yl)-2- C₂₈H₁₉FN₈O 503 A1pyridinyl)oxy)phenyl)-4-(4-fluorophenyl)-1- phthalazinamine 97N-(4-((3-(4-amino-1,3,5-triazin-2-yl)-2- C₂₈H₂₀N₈O 485 A1pyridinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine 98N-(4-((3-(2-amino-4-pyrimidinyl)-2- C₂₇H₂₀N₈OS 505 A1pyridinyl)oxy)phenyl)-4-(4-methyl-1,3-thiazol-2- yl)-1-phthalazinamine99 N-(4-(3-(2-aminopyridin-4-yl)pyridin-2- C₃₀H₂₂N₆O 483 A1yloxy)phenyl)-4-phenylphthalazin-1-amine 1002-((4-((4-(5-methyl-2-thienyl)-1- C₂₉H₂₂N₆OS 503 A1phthalazinyl)amino)phenyl)oxy)-3,4′-bipyridin-2′- amine 1012-((4-((4-(4-methyl-2-thienyl)-1- C₂₉H₂₂N₆OS 503 A1phthalazinyl)amino)phenyl)oxy)-3,4′-bipyridin-2′- amine 102N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₆H₂₁N₇O 448 A2pyridinyl)oxy)phenyl)-6-phenyl-3-pyridazinamine 1035-methyl-N-(4-((3-(2-(methylamino)-4- C₂₇H₂₃N₇O 462 A2pyrimidinyl)-2-pyridinyl)oxy)phenyl)-6-phenyl-3- pyridazinamine 104N-methyl-2-((4-((4-phenyl-5,6,7,8-tetrahydro-1- C₃₁H₂₈N₆O 501 A2phthalazinyl) amino) phenyl)oxy)-3,4′-bipyridin-2′- amine 105N-(6-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₉H₂₆N₈O 503 A2pyridinyl)oxy)-3-pyridinyl)-4-phenyl-5,6,7,8-tetrahydro-1-phthalazinamine 1066-ethyl-N-(4-((3-(2-(methylamino)-4-pyrimidinyl)- C₂₈H₂₅N₇O 476 A22-pyridinyl)oxy) phenyl)-5-phenyl-3- pyridazinamine 107N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₂H₂₉N₇O 528 A2pyridinyl)oxy) phenyl)-6-phenyl-4,5-diazatricyclo[6.2.2.0~2,7~]dodeca-2,4,6-trien-3-amine 108N-(6-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₈H₂₄N₈O 489 A2pyridinyl)oxy)-3-pyridinyl)-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine 109N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₅H₂₆N₈O 455 A2pyridinyl)oxy)phenyl)-6-(1-piperidinyl)-3- pyridazinamine 1106-(1-azepanyl)-N-(4-((3-(2-(methylamino)-4- C₂₆H₂₈N₈O 469 A2pyrimidinyl)-2-pyridinyl)oxy)phenyl)-3- pyridazinamine 111N-(4-((3-(2-amino-4-pyrimidinyl)-2- C₂₉H₂₅N₇O 488 A2pyridinyl)oxy)phenyl)-4-phenyl-5,6,7,8-tetrahydro- 1-phthalazinamine 112N-(3-fluoro-4-((3-(2-(methylamino)-4- C₃₀H₂₆FN₇O 520 A2pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenyl-5,6,7,8-tetrahydro-1-phthalazinamine 113N-(6-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)- C₂₈H₂₄N₈O 489 A23-pyridinyl)-4-phenyl-5,6,7,8-tetrahydro-1- phthalazinamine 114N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)- C₂₉H₂₄FN₇O 506 A23-fluorophenyl)-4-phenyl-5,6,7,8-tetrahydro-1- phthalazinamine 115N-(6-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)- C₂₇H₂₂N₈O 475 A23-pyridinyl)-4-phenyl-6,7-dihydro-5H- cyclopenta[d]pyridazin-1-amine 1162-((4-((4-phenyl-6,7-dihydro-5H- C₂₉H₂₄N₆O 473 A2cyclopenta[d]pyridazin-1-yl) amino)phenyl)oxy)- 3,4′-bipyridin-2′-amine117 2-((4-((4-(4-methyl-2-thienyl)-6,7-dihydro-5H- C₂₈H₂₄N₆OS 493 A2cyclopenta[d] pyridazin-1-yl)amino)phenyl)oxy)- 3,4′-bipyridin-2′-amine118 N-(4-((3-(2-amino-4-pyrimidinyl)-2- C₂₆H₂₁N₇O 448 A2pyridinyl)oxy)phenyl)-5-methyl-6-phenyl-3- pyridazinamine 119N-(4-((3-(2-amino-4-pyrimidinyl)-2- C₂₆H₂₁N₇O 448 A2pyridinyl)oxy)phenyl)-4-methyl-6-phenyl-3- pyridazinamine 120N-methyl-2-((5-((4-phenyl-6,7-dihydro-5H- C₂₉H₂₅N₇O 488 A3cyclopenta[d]pyridazin-1-yl)amino)-2-pyridinyl)oxy)-3,4′-bipyridin-2′-amine 121N-methyl-4-(2-((4-(2-pyridinylamino) phenyl)oxy)- C₂₁H₁₈N₆O 371 A33-pyridinyl)-2-pyrimidinamine 122N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₈H₂₅N₇OS 508 A3pyridinyl)oxy) phenyl)-4-(4-methyl-2-thienyl)-6,7-dihydro-5H-cyclopenta[d] pyridazin-1-amine 123N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₀H₂₇N₇O 502 B1pyridinyl)oxy) phenyl)-4-phenyl-5,6,7,8-tetrahydro- 1-phthalazinamine124 N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₀H₂₉N₇O₃ 536 B1pyridinyl)oxy) phenyl)-4,5-bis((methyloxy)methyl)-6-phenyl-3-pyridazinamine 125N-(4-(3,4′-bipyridin-2-yloxy)phenyl)-4-(4-methyl- C₂₉H₂₁N₅OS 488 B12-thienyl)-1-phthalazinamine 126N-(4-(3,4′-bipyridin-2-yloxy)phenyl)-4-(5-methyl- C₂₉H₂₁N₅OS 488 B12-thienyl)-1-phthalazinamine 127N-(4-(3,4′-bipyridin-2-yloxy)phenyl)-4-(5-chloro-2- C₂₈H₁₈ClN₅OS 508 B1thienyl)-1-phthalazinamine 128N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₁H₂₄N₆O 497 B1pyridinyl)oxy)phenyl)-4-phenyl-1-isoquinolinamine 1294-(4-fluorophenyl)-N-(4-((3-(2-(methylamino)-4- C₃₁H₂₃FN₆O 515 B1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- isoquinolinamine 130N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₉H₂₂N₆OS 503 B1pyridinyl)oxy)phenyl)-4-(2-thienyl)-1- isoquinolinamine 131N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₉H₂₂N₆OS 503 B1pyridinyl)oxy) phenyl)-4-(3-thienyl)-1- isoquinolinamine 1324-(2-fluorophenyl)-N-(4-((3-(2-(methylamino)-4- C₃₁H₂₃FN₆O 515 B1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- isoquinolinamine 1334-(3,4-dimethylphenyl)-N-(4-((3-(2-(methylamino)- C₃₃H₂₈N₆O 525 B14-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- isoquinolinamine 134N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₉H₂₃N₇OS 518 B1pyridinyl)oxy) phenyl)-4-(4-methyl-2-thienyl)-1- phthalazinamine 135N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₉H₂₃N₇OS 518 B1pyridinyl)oxy) phenyl)-4-(5-methyl-2-thienyl)-1- phthalazinamine 1364-(3-chloro-4-fluorophenyl)-N-(4-((3-(2- C₃₀H₂₁ClFN₇O 550 B1(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy) phenyl)-1-phthalazinamine137 4-(3-chloro-4-fluorophenyl)-N-(4-((3-(2- C₃₀H₂₅ClFN₇O 554 B1(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 1384-(3,5-bis(trifluoromethyl) phenyl)-N-(4-((3-(2- C₃₂H₂₁F₆N₇O 634 B1(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy) phenyl)-1-phthalazinamine139 4-(3,5-bis(trifluoromethyl) phenyl)-N-(4-((3-(2- C₃₂H₂₅F₆N₇O 638 B1(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 140N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₁H₂₂F₃N₇O 566 B1pyridinyl)oxy) phenyl)-4-(3-(trifluoromethyl) phenyl)-1-phthalazinamine141 N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₁H₂₆F₃N₇O 570 B1pyridinyl)oxy) phenyl)-4-(3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 142N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₁H₂₂F₃N₇O 566 B1pyridinyl)oxy) phenyl)-4-(4-(trifluoromethyl) phenyl)-1-phthalazinamine143 N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₁H₂₆F₃N₇O 570 B1pyridinyl)oxy) phenyl)-4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 1444-cyclopropyl-N-(4-((3-(2-(methylamino)-4- C₂₈H₂₄N₆O 461 B1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- isoquinolinamine 1454-(3-chlorophenyl)-N-(4-((3-(2-(methylamino)-4- C₃₁H₂₃ClN₆O 531 B1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- isoquinolinamine 146N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₀H₂₃N₇O 498 B1pyridinyl)oxy) phenyl)-4-(3-pyridinyl)-1- isoquinolinamine 147N-(4-((3-(2-amino-4-pyrimidinyl)-2- C₂₆H₂₃N₇OS 482 B1pyridinyl)oxy)phenyl)-4,5-dimethyl-6-(4-methyl-2-thienyl)-3-pyridazinamine 148 N-(4-((3-(2-amino-4-pyrimidinyl)-2-C₂₇H₂₃N₇O 462 B1 pyridinyl)oxy)phenyl)-4,5-dimethyl-6-phenyl-3-pyridazinamine 149 N-(3-fluoro-4-((3-(2-(methylamino)-4- C₃₁H₂₃FN₆O 515B1 pyrimidinyl)-2-pyridinyl)oxy) phenyl)-4-phenyl-1- isoquinolinamine150 N-(4-((3-(2-amino-4-pyrimidinyl)-2- C₃₀H₂₂N₆O 483 B1pyridinyl)oxy)phenyl)-4-phenyl-1-isoquinolinamine 1514-(4-methyl-2-thienyl)-N-(4-((3-(4-pyrimidinyl)-2- C₂₈H₂₀N₆OS 489 B1pyridinyl)oxy)phenyl)-1-phthalazinamine 1524-(5-methyl-2-thienyl)-N-(4-((3-(4-pyrimidinyl)-2- C₂₈H₂₀N₆OS 489 B1pyridinyl)oxy)phenyl)-1-phthalazinamine 1534-(4-methyl-2-thienyl)-N-(4-((3-(4-pyrimidinyl)-2- C₂₈H₂₀N₆OS 489 B1pyridinyl)oxy)phenyl)-1-phthalazinamine 1544-(5-methyl-2-thienyl)-N-(4-((3-(4-pyrimidinyl)-2- C₂₈H₂₀N₆OS 489 B1pyridinyl)oxy)phenyl)-1-phthalazmamine 1555-(4-chlorophenyl)-N-(4-((3-(2-(methylamino)-4- C₂₉H₂₁ClN₈O 533 B1pyrimidinyl)-2-pyridinyl)oxy)phenyl)pyrido[2,3- d]pyridazin-8-amine 156N-(4-((3-(2-amino-4-pyrimidinyl)-2- C₂₇H₂₂FN₇O 480 B1pyridinyl)oxy)phenyl)-6-(4-fluorophenyl)-4,5- dimethyl-3-pyridazinamine157 N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₇H₂₃N₇O 462 B1pyridinyl)oxy)phenyl)-6-(2-methylphenyl)-3- pyridazinamine 158N-methyl-2-((5-((4-(4-methyl-2-thienyl)-1- C₂₉H₂₃N₇OS 518 B1phthalazinyl)amino)-2-pyridinyl)oxy)-3,4′- bipyridin-2′-amine 1592-((5-((4-(3-chlorophenyl)-1-phthalazinyl)amino)- C₃₀H₂₂ClN₇O 532 B12-pyridinyl)oxy)-N-methyl-3,4′-bipyridin-2′-amine 160N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₇H₂₁N₉OS 520 B1pyridinyl)oxy)phenyl)-8-(4-methyl-2-thienyl)pyrazino[2,3-d]pyridazin-5-amine 161N-methyl-2-((5-((4-(5-methyl-2-thienyl)-1- C₂₉H₂₃N₇OS 518 B1phthalazinyl)amino)-2-pyridinyl)oxy)-3,4′- bipyridin-2′-amine 1624-(5-methyl-2-thienyl)-N-(4-((3-(1H-pyrrolo[2,3- C₃₁H₂₂N₆OS 527 B1b]pyridin-4-yl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 1632-((5-((4-(5-chloro-2-thienyl)-1- C₂₈H₂₀ClN₇OS 538 B1phthalazinyl)amino)-2-pyridinyl)oxy)-N-methyl- 3,4′-bipyridin-2′-amine164 N-(4-((3-(2-amino-4-pyrimidinyl)-2- C₂₈H₁₉F₂N₇OS 540 B1pyridinyl)oxy)phenyl)-6,7-difluoro-4-(4-methyl-2-thienyl)-1-phthalazinamine 1654-(4-fluorophenyl)-N-(4-((3-(2-(methylamino)-4- C₃₀H₂₂FN₇O 516 B1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 166N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₀H₂₃N₇O 498 B1pyridinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine 167N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₈H₂₁N₇OS 504 B1pyridinyl)oxy)phenyl)-4-(3-thienyl)-1- phthalazinamine 1684-(2-fluorophenyl)-N-(4-((3-(2-(methylamino)-4- C₃₀H₂₂FN₇O 516 B1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 169N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₁H₂₂F₃N₇O 566 B1pyridinyl)oxy)phenyl)-4-(2- (trifluoromethyl)phenyl)-1-phthalazinamine170 4-(2-chlorophenyl)-N-(4-((3-(2-(methylamino)-4- C₃₀H₂₂ClN₇O 532 B1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 171N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₉H₂₂N₈O 499 B1pyridinyl)oxy)phenyl)-4-(3-pyridinyl)-1- phthalazinamine 172N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₉H₂₂N₈O 499 B1pyridinyl)oxy)phenyl)-4-(4-pyridinyl)-1- phthalazinamine 173N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₁H₂₉N₇O₂ 532 B1pyridinyl)oxy)phenyl)-4-(3-(methyloxy)phenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 174N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₁H₂₉N₇O₂ 532 B1pyridinyl)oxy)phenyl)-4-(4-(methyloxy)phenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 175N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₁H₂₉N₇O 516 B1pyridinyl)oxy)phenyl)-4-(3-methylphenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 176N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₁H₂₉N₇O 516 B1pyridinyl)oxy)phenyl)-4-(4-methylphenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 177N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₈H₂₅N₇OS 508 B1pyridinyl)oxy)phenyl)-4-(3-thienyl)-5,6,7,8-tetrahydro-1-phthalazinamine 1784-(3,4-dimethylphenyl)-N-(4-((3-(2-(methylamino)- C₃₂H₃₁N₇O 530 B14-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 179N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₁H₂₅N₇O 512 B1pyridinyl)oxy)phenyl)-4-(3-methylphenyl)-1- phthalazinamine 180N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₁H₂₅N₇O 512 B1pyridinyl)oxy)phenyl)-4-(4-methylphenyl)-1- phthalazinamine 1814-(3,4-dimethylphenyl)-N-(3-fluoro-4-((3-(2- C₃₂H₂₆FN₇O 544 B1(methylamino)-4-pyrimidinyl)-2- pyridinyl)oxy)phenyl)-1-phthalazinamine182 N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₉H₂₅N₇O 488 B1pyridinyl)oxy)phenyl)-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine 1834-(3,5-dimethylphenyl)-N-(4-((3-(2-(methylamino)- C₃₂H₂₇N₇O 526 B14-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 1844-(3,5-dimethylphenyl)-N-(4-((3-(2-(methylamino)- C₃₂H₃₁N₇O 530 B14-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 185N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₉H₂₇N₇OS 522 B1pyridinyl)oxy)phenyl)-4-(5-methyl-2-thienyl)-5,6,7,8-tetrahydro-1-phthalazinamine 186N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₁H₂₉N₇O₂ 532 B1pyridinyl)oxy)phenyl)-4-(2-(methyloxy)phenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 187N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₈H₂₅N₇OS 508 B1pyridinyl)oxy)phenyl)-4-(2-thienyl)-5,6,7,8-tetrahydro-1-phthalazinamine 1883-(4-((4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₁H₂₆N₈O 527 B1pyridinyl)oxy)phenyl)amino)-5,6,7,8-tetrahydro-1-phthalazinyl)benzonitrile 1894-(4-((4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₁H₂₆N₈O 527 B1pyridinyl)oxy)phenyl)amino)-5,6,7,8-tetrahydro-1-phthalazinyl)benzonitrile 1904-(4-fluorophenyl)-N-(4-((3-(2-(methylamino)-4- C₃₀H₂₆FN₇O 520 B1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 191N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₁H₂₅N₇O 512 B1pyridinyl)oxy)phenyl)-4-(2-methylphenyl)-1- phthalazinamine 192N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₁H₂₉N₇O 516 B1pyridinyl)oxy)phenyl)-4-(2-methylphenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 1934-(3-chlorophenyl)-N-(4-((3-(2-(methylamino)-4- C₃₀H₂₆ClN₇O 536 B1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 1944-(4-chlorophenyl)-N-(4-((3-(2-(methylamino)-4- C₃₀H₂₆ClN₇O 536 B1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 1954-(3-chlorophenyl)-N-(4-((3-(2-(methylamino)-4- C₃₀H₂₂ClN₇O 532 B1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 1964-(4-chlorophenyl)-N-(4-((3-(2-(methylamino)-4- C₃₀H₂₂ClN₇O 532 B1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 197N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₉H₂₇N₇OS 522 B1pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-5,6,7,8-tetrahydro-1-phthalazinamine 1984-(4-fluoro-1-piperidinyl)-N-(4-((3-(2- C₂₉H₂₇FN₈O 523 B1(methylamino)-4-pyrimidinyl)-2- pyridinyl)oxy)phenyl)-1-phthalazinamine199 4-(3-fluorophenyl)-N-(4-((3-(2-(methylamino)-4- C₃₀H₂₂FN₇O 516 B1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 2004-(3,4-difluorophenyl)-N-(4-((3-(2-(methylamino)- C₃₀H₂₁F₂N₇O 534 B14-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 2014-(3,4-dichlorophenyl)-N-(4-((3-(2-(methylamino)- C₃₀H₂₁Cl₂N₇O 566 B14-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 2022-((4-((4-(4-chlorophenyl)-1- C₃₁H₂₃ClN₆O 531 B1phthalazinyl)amino)phenyl)oxy)-N-methyl-3,4′- bipyridin-2′-amine 2032-((4-((4-(3-chloro-4-fluorophenyl)-1- C₃₁H₂₂ClFN₆O 549 B1phthalazinyl)amino)phenyl)oxy)-N-methyl-3,4′- bipyridin-2′-amine 2044-(3-chlorophenyl)-N-(4-((3-(2-(methylamino)-4- C₂₉H₂₄ClN₇O 522 B1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine 205 2-((4-((4-(3-chlorophenyl)-1-C₃₁H₂₃ClN₆O 531 B1 phthalazinyl)amino)phenyl)oxy)-N-methyl-3,4′-bipyridin-2′-amine 206 4-(3,4-dichlorophenyl)-N-(4-((3-(2-(methylamino)-C₃₀H₂₅Cl₂N₇O 570 B1 4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 207N-methyl-2-((4-((4-(4-methyl-2-thienyl)-1- C₃₀H₂₄N₆OS 517 B1phthalazinyl)amino)phenyl) oxy)-3,4′-bipyridin-2′- amine 208N-methyl-2-((4-((4-(5-methyl-2-thienyl)-1- C₃₀H₂₄N₆OS 517 B1phthalazinyl)amino)phenyl) oxy)-3,4′-bipyridin-2′- amine 2094-(5-chloro-2-thienyl)-N-(4-((3-(2-(methylamino)- C₂₈H₂₀ClN₇OS 538 B14-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 2104-(5-chloro-2-thienyl)-N-(4-((3-(2-(methylamino)- C₂₈H₂₄ClN₇OS 542 B14-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 211 N-(4-((3-(2-amino-4-pyrimidinyl)-2-C₂₈H₂₀N₈O 485 B1 pyridinyl)oxy)phenyl)-4-(3-pyridinyl)-1-phthalazinamine 212 N-(4-((3-(2-amino-4-pyrimidinyl)-2- C₂₇H₁₉N₇OS 490B1 pyridinyl)oxy)phenyl)-4-(2-thienyl)-1- phthalazinamine 213N-(4-((3-(2-amino-4-pyrimidinyl)-2- C₂₈H₂₁N₇OS 504 B1pyridinyl)oxy)phenyl)-4-(5-methyl-2-thienyl)-1- phthalazinamine 214N-(6-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)- C₂₇H₂₀N₈OS 505 B13-pyridinyl)-4-(4-methyl-2-thienyl)-1- phthalazinamine 215N-(4-((3-(2-((3-(4-methyl-1- C₃₆H₃₇N₉OS 644 B1piperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1- phthalazinamine 2164-(1-benzothien-3-yl)-N-(4-((3-(2-(methylamino)- C₃₂H₂₃N₇OS 554 B14-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 2174-(1-benzothien-2-yl)-N-(4-((3-(2-(methylamino)- C₃₂H₂₃N₇OS 554 B14-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 2184-(1H-indol-5-yl)-N-(4-((3-(2-(methylamino)-4- C₃₂H₂₄N₈O 537 B1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 2194-(1-benzothien-3-yl)-N-(4-((3-(2-(methylamino)- C₃₂H₂₇N₇OS 558 B14-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 2204-(1-benzothien-2-yl)-N-(4-((3-(2-(methylamino)- C₃₂H₂₇N₇OS 558 B14-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-5,6,7,8-tetrahydro-1-phthalazinamine 2214-(4-chlorophenyl)-N-(4-((3-(2-(methylamino)-4- C₂₉H₂₄ClN₇O 522 B1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine 222N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₉H₂₆N₈O 503 B2pyridinyl)oxy)phenyl)-4-(2-pyridinyl)-5,6,7,8-tetrahydro-1-phthalazinamine 2234-(cyclopropylethynyl)-N-(4-((3-(2-(methylamino)- C₂₉H₂₃N₇O 486 B34-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 224N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₉H₂₉N₉O 520 B4pyridinyl)oxy)phenyl)-4-(4-methyl-1-piperazinyl)- 1-phthalazinamine 225N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₈H₂₆N₈O 491 B4pyridinyl)oxy)phenyl)-4-(1-pyrrolidinyl)-1- phthalazinamine 2264-(1-azepanyl)-N-(4-((3-(2-(methylamino)-4- C₃₀H₃₀N₈O 519 B4pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 227N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₀H₃₀N₈O 519 B4pyridinyl)oxy)phenyl)-4-(3-methyl-1-piperidinyl)- 1-phthalazinamine 228N-(4-((3-(2-amino-4-pyrimidinyl)-2- C₂₈H₂₇N₉O 506 B4pyridinyl)oxy)phenyl)-4-(4-methyl-1-piperazinyl)- 1-phthalazinamine 2294-(4-ethyl-1-piperazinyl)-N-(4-((3-(2- C₃₀H₃₁N₉O 534 B4(methylamino)-4-pyrimidinyl)-2- pyridinyl)oxy)phenyl)-1-phthalazinamine230 N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₃₁H₃₃N₉O 548 B4pyridinyl)oxy)phenyl)-4-(4-(1-methylethyl)-1-piperazinyl)-1-phthalazinamine 231N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₉H₃₂N₈O 509 B5pyridinyl)oxy)phenyl)-4-(1-piperidinyl)-5,6,7,8-tetrahydro-1-phthalazinamine 232N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₈H₂₂N₈OS 519 B6pyridinyl)oxy)phenyl)-4-(5-methyl-1,3-thiazol-2- yl)-1-phthalazinamine233 N-(4-((3-(2-amino-4-pyrimidinyl)-2- C₂₇H₂₀N₈OS 505 B6pyridinyl)oxy)phenyl)-4-(5-methyl-1,3-thiazol-2- yl)-1-phthalazinamine234 4-(1H-imidazol-1-yl)-N-(4-((3-(2-(methylamino)-4- C₂₇H₂₁N₉O 488 B7pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 235N-(4-((3-(2-(methylamino)-4-pyrimidinyl)-2- C₂₇H₂₁N₉O 488 B7pyridinyl)oxy)phenyl)-4-(1H-pyrazol-1-yl)-1- phthalazinamine 236N-(4-((3-(2-amino-4-pyrimidinyl)-2- C₂₇H₂₁N₉O 488 B7pyridinyl)oxy)phenyl)-4-(4-methyl-1H-pyrazol-1- yl)-1-phthalazinamine237 N-methyl-2-((4-((4-phenyl-1- C₃₂H₂₅N₅O 496 Cphthalazinyl)methyl)phenyl)oxy)-3,4′-bipyridin-2′- amine 238N-(4-((3-(5-amino-1H-pyrazol-4-yl)-2- C₂₈H₂₁N₇O 472 Cpyridinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine 239N-(4-(3-(2-(2-(dimethylamino)ethylamino)pyrimidin- C₃₃H₃₀N₈O 555 D4-yl)pyridin-2- yloxy)phenyl)-4-phenylphthalazin-1-amine 240N-(4-(3-(2-(3-(diethylamino)propylamino)pyrimidin- C₃₆H₃₆N₈O 597 D4-yl)pyridin-2- yloxy)phenyl)-4-phenylphthalazin-1-amine

Example Method E

Synthesis ofN-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-(pyrrolidin-1-ylmethyl)phenyl)phthalazin-1-amine

A 25 mL RBF under nitrogen was charged with4-(4-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenylamino)phthalazin-1-yl)benzaldehyde(90 mg, 0.18 mmol), pyrrolidine (125 mg, 1.8 mmol) and MeOH (3.5 mL,0.05 M). HOAc was added (0.02 mL, 0.36 mmol) and the reaction mixturewas stirred at RT for 2 hrs. The reaction mixture was cooled to 0° C.and sodium triacetoxyborohydride (186 mg, 0.90 mmol) was addedportionwise. The mixture was stirred at RT overnight, then cooled to 0°C. and basified with aqueous sodium bicarbonate and the product wasextracted into DCM. The organic layers were collected, dried over sodiumsulfate, filtered and concentrated to give brown residue. The cruderesidue was purified by Gilson reverse phase liquid chromatography(5%-85% CH₃CN/H₂O+0.1% TFA). Product-containing fractions were combinedand basified with aqueous sodium bicarbonate. This was extracted withEtOAc, dried over sodium sulfate, filtered, concentrated under reducedpressure, and dried under high vacuum to affordN-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-(pyrrolidin-1-ylmethyl)phenyl)phthalazin-1-amineas a light yellow solid. MS m/z=567 [M+H]⁺. Calc'd for C₃₄H₃₀N₈O: 566.7.

Example Method F

Synthesis of3-(4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylamino)propyldihydrogen phosphate dihydrochloride Step 1: Preparation ofdi-tert-butyl3-(4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylamino)propylphosphate

A 15 mL RBF under nitrogen was charged with3-(4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylamino)propan-1-ol(130 mg, 0.24 mmol) in DMA (1.2 mL, 0.24 mmol). To this was addeddi-tert-butyl diethylphosphoramidite (0.14 mL, 0.57 mmol) and1H-tetrazole (1.1 mL, 0.49 mmol). The reaction mixture was stirred at RTfor 2 hrs, then cooled to −5° C. and hydrogen peroxide −30 wt. % inwater (0.05 mL, 0.51 mmol) added slowly via syringe. The reaction waswarmed up to RT and stirred for 2 hrs. The reaction was cooled back to−5° C. and quenched with saturated aqueous solution of sodiumthiosulfate. The product was extracted into EtOAc, and the organic layerwas collected, dried over sodium sulfate and concentrated to afford acrude yellow residue. The residue was purified by ISCO silica gelchromatography (2-5% MeOH/DCM), and the purified fractions were furtherpurified by Gilson RPLC in system (15%-85% CH₃CN/H₂O/0.1% TFA) to afforddi-tert-butyl3-(4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylamino)propylphosphate. MS m/z=734 [M+H]⁺. Calc'd for C₄₀H₄₄N₇O₅P: 733.8.

Step 2: Preparation of3-(4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylamino)propyldihydrogen phosphate dihydrochloride

To a solution of di-tert-butyl3-(4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylamino)propylphosphate (95 mg, 0.13 mmol) in 1,4-dioxane (3.7 ml, 0.04 M) undernitrogen was added 4M HCl in Dioxane (0.23 mL, 0.91 mmol). Reactionstirred at RT for 18 hrs. The mixture appeared heterogeneous, and thesolids were filtered, washed with dioxane and ether, and dried underreduced pressure to afford3-(4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylamino)propyldihydrogen phosphate dihydrochloride as a yellow solid. Mass of thetitle compound was obtained as the free base: MS m/z=622 [M+H]⁺. Calc'dfor C₃₂H₃₀C₁₂N₇O₅P: 621.6.

The following additional exemplary compounds should further assist inunderstanding the scope of the invention.

Example 241

Synthesis of4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)-1H-pyrazole-3-carboxamideStep 1. Preparation of tert-butyl4-bromo-3-cyano-1H-pyrazole-1-carboxylate

In a 20 mL sealed tube was dissolved 4-bromo-1h-pyrazole-3-carbonitrile(1.0 g, 5.8 mmol) in THF (10 mL). The mixture was cooled to 0° C., uponwhich NaH (60% in mineral oil; 0.42 g, 12 mmol) was added, and stirredfor 5 minutes. To the mixture was added di-tert-butyl dicarbonate (2.5g, 12 mmol) and the mixture was stirred at 0° C. for 3 h, then quenchedwith water, extracted into EtOAc, and the organic layer was washed1×H₂O, 1× saturated NaCl, dried with Na₂SO₄, filtered through frittedfunnel and concentrated. The crude material was purified by normal phasesilica gel chromatography using 10-100% EtOAc/Hexanes. The product wasconcentrated to yield tert-butyl4-bromo-3-cyano-1H-pyrazole-1-carboxylate as light yellow solid.

Step 2. Preparation of4-(2-(4-aminophenoxy)pyridin-3-yl)-1H-pyrazole-3-carbonitrile

Dioxane (2.0 mL) was added to a 20 mL sealed tube. The tube was purgedwith nitrogen for 5 minutes. To this was added tert-butyl4-bromo-3-cyano-1H-pyrazole-1-carboxylate (0.100 g, 0.368 mmol),4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)benzenamine(0.229 g, 0.735 mmol), and sodium carbonate (2.0 M in water) (0.667 mL).Palladium(II) acetate (0.008 g, 0.037 mmol) and tri-t-butylphosphoniumtetrafluoroborate (0.021 g, 0.074 mmol) was added and the tube waspurged with nitrogen, sealed, and heated to 100° C. for 17 hours. Thereaction was cooled to RT, concentrated and passed through a pad ofsilica with the aid of 90:10:1 (CH₂Cl₂:MeOH:NH₄OH). The eluent wasconcentrated to yield4-(2-(4-aminophenoxy)pyridin-3-yl)-1H-pyrazole-3-carbonitrile as lightbrown solid. MS m/z=278 [M+1]⁺. Calc'd for C₁₅H₁₁N₅O: 277.28.

Step 3. Preparation of4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)-1H-pyrazole-3-carbonitrile

In a 20-mL sealed tube was dissolved4-(2-(4-aminophenoxy)pyridin-3-yl)-1H-pyrazole-3-carbonitrile (0.120 g,0.433 mmol) in t-BuOH (1.0 mL). Then 1-chloro-4-phenylphthalazine (0.104g, 0.433 mmol) was added and the mixture was stirred at 100° C. for 3days. The reaction was cooled to RT, concentrated and purified on aGilson reverse phase chromatography system. The title compound wasextracted into CH₂Cl₂, washed 1× saturated NaHCO₃ 1×H₂O, dried overNa₂SO₄, filtered through fritted funnel and concentrated. The titlecompound was further purified by silica gel chromatography using 10-100%EtOAc/Hexanes to afford4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)-1H-pyrazole-3-carbonitrileas light yellow solid. MS m/z=482 [M+1]⁺. Calc'd for C₂₉H₁₉N₇O: 481.51.

Step 4. Preparation of4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)-1H-pyrazole-3-carboxamide

In a 20-mL sealed tube was dissolved4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)-1H-pyrazole-3-carbonitrile(0.070 g, 0.145 mmol) in DMSO (1.0 mL). To this was added potassiumcarbonate (0.024 g, 0.174 mmol) and hydrogen peroxide (0.445 mL, 14.5mmol) and the mixture was stirred at 20° C. for 3 days and quenched withwater. The product was extracted into EtOAc, washed 1× saturated NaHCO₃,1×H₂O, dried over Na₂SO₄, filtered through fritted funnel andconcentrated. The title compound was purified using a Gilson reversephase liquid chromatography system. The product fractions were extractedinto CH₂Cl₂. The organic layers were washed organics 1× saturatedNaHCO₃, 1×H₂O, dried with Na₂SO₄, filtered through fritted funnel andconcentrated to yield4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)-1H-pyrazole-3-carboxamideas light yellow solid. MS m/z=500 [M+1]⁺. Calc'd for C₂₉H₂₁N₇O₂: 499.52.

Example 242

Synthesis ofN-(4-(3-(2-(methylamino)pyridin-4-yl)pyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amineStep 1. Preparation of 4-(4-phenylphthalazin-1-ylamino)phenol

A pressure bottle was charged with 4-aminophenol (0.453 g, 0.416 mmol),1-chloro-4-phenylphthalazine (1.00 g, 0.416 mmol) and 16.8 mL ofbenzene. The bottle was sealed and heated to 100° C. for 25 h. Thereaction mixture was concentrated. The crude material was dissolved inmethanol and was purified by Gilson reverse phase liquid chromatography,5-75% ACN/H2O/0.1% TFA over 14 min. The product-containing fractionswere combined, brought to basic pH by addition of 1M NaHCO₃, andextracted with dichloromethane. The organic portion was dried withMgSO₄, filtered and concentrated to provide4-(4-phenylphthalazin-1-ylamino)phenol as a yellow solid. MS m/z=314[M+H]⁺. Calc'd for C₂₀H₁₅N₃O: 313.35.

Step 2. Preparation ofN-(4-(3-bromopyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine

A resealable reaction tube was charged with cesium carbonate (0.873 g,0.268 mmol), 3-bromo-4-chloropyridine hydrochloride (0.205 g, 0.894mmol) and 4-(4-phenylphthalazin-1-ylamino)phenol (0.280 g, 0.894 mmol)and purged with nitrogen for several minutes. 1.8 mL of DMSO was added,the tube was sealed, and the reaction mixture was heated to 130° C. for3 h. Upon cooling the mixture was diluted with EtOAc and washed withwater. The aqueous portion was extracted with EtOAc, and the combinedorganic portions were dried with MgSO₄ and concentrated.N-(4-(3-bromopyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine wasisolated as an orange solid. MS m/z=470 [M+H]⁺. Calc'd for C₂₅H₁₇BrN₄O:469.33.

Step 3. Preparation ofN-(4-(3-(2-fluoropyridin-4-yl)pyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine

A resealable reaction tube was charged with tri-tert-butylphosphoniumtetrafluoroborate (0.024 g, 0.082 mmol), palladium (II) acetate (0.009g, 0.041 mmol), 2-fluoropyridine-4-boronic acid (0.086 g, 0.614 mmol)and N-(4-(3-bromopyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine(0.192 mg, 0.409 mmol) and was purged with nitrogen for several minutes.1.2 mL of dioxane and 2.0 M aqueous sodium carbonate (0.614 mL, 0.123mmol) were added, the tube was sealed, and the reaction mixture washeated to 100° C. for 48 h. The mixture was diluted with EtOAc andwashed with water. The organic portion was dried with MgSO₄ andconcentrated. Purification by Gilson reverse phase liquid chromatography(5-70% ACN/water/0.1% TFA over 14 min) providedN-(4-(3-(2-fluoropyridin-4-yl)pyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amineas a mixture with the hydrodehalogenation product ofN-(4-(3-bromopyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine.

Step 4. Preparation ofN-(4-(3-(2-(methylamino)pyridin-4-yl)pyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine

A high pressure steel bomb was charged withN-(4-(3-(2-fluoropyridin-4-yl)pyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine(0.115 g, 0.237 mmol), potassium carbonate (0.049 g, 0.355 mol) and 3.0mL of THF. The bomb was sealed, cooled to 0° C. and pressurized withmethylamine gas. The reaction mixture was allowed to warm to RT, andheated at 80° C. for 45 h. Upon cooling, the reaction mixture wasfiltered through a fritted funnel, washed with MeOH, and concentrated.This mixture was purified by silica gel chromatography, (ISCO, 40 gcolumn 0-10% MeOH/dichloromethane) to provideN-(4-(3-(2-(methylamino)pyridin-4-yl)pyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amineas a light yellow solid. MS m/z=497 [M+H]⁺. Calc'd for C₃₁H₂₄N₆O:496.56.

Example 243

Synthesis of4-phenyl-N-(4-(5-(pyridin-4-yl)pyrimidin-4-yloxy)phenyl)phthalazin-1-amineStep 1. Preparation of 5-iodopyrimidin-4-ol

The title compound was prepared following the literature reference:Chem. Pharm. Bull. 1986, 34, 2719-2714. As described therein, to a lightyellow solution of pyrimidin-4-ol (10.0 g, 104 mmol) in sodium hydride6.0 M (23.1 ml, 139 mmol) and water (77 mL) was added iodine (26.4 g,104 mmol). The mixture was heated to 80° C., with an air-cooledcondenser, and became quite thick after 5 min. After 30 min, the mixturewas easy to stir and red/purplish in color. The reaction was heatedovernight, then cooled and neutralized by a small amount of AcOH. Theprecipitate was collected by filtration, rinsed with 100 mL water, andwas dried in vacuo to give 5-iodopyrimidin-4-ol as a tan solid. MSm/z=223 [M+H]⁺. Calc'd for C₄H₃₁N₂O: 222.0.

Step 2. Preparation of 4-chloro-5-iodopyrimidine

A mixture of 5-iodopyrimidin-4-ol (14.9 g, 67.1 mmol) in phosphorousoxychloride (25.0 ml, 268 mmol) with a water-cooled reflux condenserfitted with a drying tube was heated to reflux in a 135° C. bath for 3h. The purple solution was cooled until warm and poured onto ice withswirling. The ice-cold mixture was basified with 6N NaOH, with additionof ice to maintain the cool temperature. The resulting brown precipitatewas collected by filtration, rinsed with water, and dried in vacuo togive 4-chloro-5-iodopyrimidine as an orange solid. MS m/z=241 [M+H]⁺.Calc'd for C₄H₂₁ClN₂: 240.4.

Step 3. Preparation ofN-(4-(5-iodopyrimidin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine

To a brown mixture of cesium carbonate (2.79 g, 8.58 mmol) and4-(4-phenylphthalazin-1-ylamino)phenol hydrochloride (1.00 g, 2.86 mmol)in 10 mL DMSO was added 4-chloro-5-iodopyrimidine (0.687 g, 2.86 mmol).The reaction was allowed to stir at RT for 1 h. The reaction was heatedto and maintained at 70° C. overnight. The reaction was cooled anddiluted with water. The solid was filtered and dried in vacuo to giveN-(4-(5-iodopyrimidin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine as agray solid. MS m/z=518 [M+H]⁺. Calc'd for C₂₄H₁₆IN₅O: 517.3.

Step 4. Preparation of4-phenyl-N-(4-(5-(pyridin-4-yl)pyrimidin-4-yloxy)phenyl)phthalazin-1-amine

A slurry of 4-pyridylboronic acid (0.0950 g, 0.773 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.0141 g,0.0193 mmol), andN-(4-(5-iodopyrimidin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine (0.200g, 0.387 mmol) and sodium carbonate 2.0 M in H₂O (0.387 ml, 0.773 mmol)in 1.5 mL dioxane was flushed with nitrogen, sealed, and heated to 80°C. The reaction became dark and solids dissolved after 1 h. After 3 h,the reaction was judged complete. The reaction was cooled and dilutedwith DCM and water. The resulting aqueous emulsion was extracted 4×DCM.The combined organics were dried over anhyd sodium sulfate, filtered,and concentrated in vacuo. The material was adsorbed onto 1.8 g silicagel from MeOH/DCM, dried, and purified by silica gel chromatography(0-60-100% 90/10 DCM/MeOH in DCM) to give4-phenyl-N-(4-(5-(pyridin-4-yl)pyrimidin-4-yloxy)phenyl)phthalazin-1-amineas a tan solid. MS m/z=469 [M+H]⁺. Calc'd for C₂₉H₂₀N₆O: 468.5.

Example 244

Synthesis ofN-methyl-4-(2-(4-(4-phenylphthalazin-1-yloxy)phenoxy)pyridin-3-yl)pyrimidin-2-amineStep 1. Preparation ofN-methyl-4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridin-3-yl)pyrimidin-2-amine

1,1′-Bis(diphenylphosphino)ferrocene-palladium dichloride (0.0453 g,0.0618 mmol), bis(pinacolato)diboron (0.330 g, 1.30 mmol),4-(2-(4-iodophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.500 g,1.24 mmol), and potassium acetate (0.243 g, 2.47 mmol) were combined ina sealed tube under nitrogen. 5 mL Dioxane was added, and the orangemixture was sealed and heated to and maintained at 75° C. After 5 h, atrace of desired product was evident by LCMS. The reaction was heated to100° C., overnight. The temperature was raised to 120° C. After 16 h,the reaction was filtered through celite, rinsing with EtOAc, andconcentrated in vacuo to a dark oil, which was purified by silica gelchromatography (50-100% EtOAc/hexanes) to giveN-methyl-4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridin-3-yl)pyrimidin-2-amine.MS m/z=405 [M+H]⁺. Calc'd for C₂₂H₂₅BN₄O₃: 404.3.

Step 2. Preparation of4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenol

To a solution ofN-methyl-4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridin-3-yl)pyrimidin-2-amine(0.414 g, 1.02 mmol) in 2 mL EtOH at 0° C. was added hydrogen peroxide,30 wt. % solution in water (0.984 ml, 10.2 mmol). The reaction wasallowed to warm to ambient temperature. After 1 h, the reaction wasdiluted with DCM, and the layers were separated. The aqueous layer wasextracted with 5% MeOH/DCM. The combined organics were dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by silica gel chromatography, (EtOAc/hexanes) togive 4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenol as awhite solid. MS m/z=295 [M+H]⁺. Calc'd for C₁₆H₁₄N₄O₂: 294.3.

Step 3. Preparation ofN-methyl-4-(2-(4-(4-phenylphthalazin-1-yloxy)phenoxy)pyridin-3-yl)pyrimidin-2-amine

A mixture of 1-chloro-4-phenylphthalazine (0.0900 g, 0.374 mmol),4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenol (0.110 g,0.374 mmol), and potassium carbonate (0.129 g, 0.934 mmol) in 1 mL DMSOwas heated in a sealed tube for 1 h. Upon cooling, a white precipitateformed. The material was partitioned between water and DCM. The organiclayer was dried over sodium sulfate, filtered, and concentrated in vacuoto give a crude solid, which was suspended in MeOH, sonicated, filteredand dried to giveN-methyl-4-(2-(4-(4-phenylphthalazin-1-yloxy)phenoxy)pyridin-3-yl)pyrimidin-2-amineas a white solid. MS m/z=499 [M+H]⁺. Calc'd for C₃₀H₂₂N₆O₂: 498.5.

Example 245

Synthesis of4-(4-chlorothiophen-2-yl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amineStep 1. Preparation of (3-chlorothiophen-2-yl)trimethylsilane

The title compound was prepared according to the procedure described inWO9412505. To a solution of 3-chlorothiophene (7.00 g, 59.0 mmol) in 60mL anhydrous THF under nitrogen was added n-butyllithium, 2.5 M inhexanes (23.6 ml, 59.0 mmol) dropwise from a plastic syringe over 15min. The reaction became cloudy with a white ppt. The reaction wasallowed to stir for 40 min, at which point trimethylsilyl chloride (8.24ml, 64.9 mmol) was added dropwise via syringe over 5 min. The mixturewas allowed to stir for 10 min, and was then warmed to 0° C. for 10 min,and 7 mL water and 35 mL brine were added. The mixture was diluted withEtOAc, and the layers separated. The aqueous layer was extracted oncewith EtOAc. The combined organics were dried over anhydrous sodiumsulfate, filtered, and concentrated in vacuo to give(3-chlorothiophen-2-yl)trimethylsilane as a yellow oil.

Step 2. Preparation of 4-chloro-5-(trimethylsilyl)thiophen-2-ylboronicacid

To a solution of diisopropyl amine (1.8 ml, 13 mmol) at 0° C. in 50 mLanhdrous THF under nitrogen was added butyllithium, 2.5 M in hexanes(4.6 ml, 12 mmol). The solution was allowed to stir 5 min and then wascooled to −78° C. (3-Chlorothiophen-2-yl)trimethylsilane (2.0 g, 10mmol) in 5 mL THF at RT was added slowly via cannula, dropwise, overabout 10 min. The resulting solution was allowed to stir for 30 min, atwhich point trimethyl borate (2.4 ml, 21 mmol) was added dropwise. Thesolution was allowed to stir for 1 h, and was then warmed to 0° C. andquenched by the addition of 25 mL of 2NHCl, and warmed to ambienttemperature with stirring. The mixture was extracted three times withDCM, and the combined organics were dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to give a semisolid. Purification bysilica gel chromatography, (0-40% EtOAc/hexanes) provided4-chloro-5-(trimethylsilyl)thiophen-2-ylboronic acid as an off-whitesolid.

Step 3. Preparation of4-(4-chlorothiophen-2-yl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine

1,1′-Bis(diphenylphosphino)ferrocene-palladium dichloride (0.0401 g,0.0548 mmol), 4-chloro-5-(trimethylsilyl)thiophen-2-ylboronic acid(0.161 g, 0.685 mmol),4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine(0.250 g, 0.548 mmol), sodium carbonate 2M in H₂O (0.548 ml, 1.10 mmol)in 3 mL dioxane was heated in a sealed tube to 90° C. After 3 h 0.75equiv boronic acid was added and the reaction was heated for 16 h. Thereaction was cooled to ambient temperature and partitioned between EtOAcand 1N NaOH. The aqueous layer was extracted 3× with EtOAc. The combinedorganics were dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo. The resulting oil was purified by silica gelchromatography (0-100% EtOAc/DCM) to give a to give a mixture of4-(4-chloro-5-(trimethylsilyl)thiophen-2-yl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amineand4-(4-chlorothiophen-2-yl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amineas a yellow oil. This material was taken up in 2.5 mL THF and water(0.061 ml, 3.4 mmol) was added, followed by tetrabutylammonium fluoride,1.0 M in THF (0.45 ml, 0.45 mmol). The reaction was stirred for 16 h,and was then diluted with EtOAc/brine. The organic layer was dried overanhydrous sodium sulfate, filtered, and concentrated to a yellow oil. 4mL MeOH was added, producing a yellow solution, and this was sonicatedfor several minutes until a thick precipitate formed. Additionalmethanol was added, and the mixture was filtered. The precipitate wasrinsed with 2×MeOH and dried in vacuo to give4-(4-chlorothiophen-2-yl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amineas a yellow solid. MS m/z=538 [M+H]⁺. Calc'd for C₂₈H₂₀ClN₇OS: 538.0.

The following compounds (Examples 246-460) in Table II were made, asnoted in table I, by one of the exemplified methods A1, A2, A3, B1, B2,B3, B4, B5, B6, B7, C or D described above. The MS data represent themass (M+H⁺) found for that example.

TABLE II AurA/TP pHH3 Ex. X2_IC50_IP AurB_IC50_IP EC50_IP MS No. Name(Avg) (Avg) (Avg) Data Method 246 N-(4-((3-(2-amino-4-pyrimidinyl)-2- ++++ + 510 A2 pyridinyl)oxy)phenyl)-4,6-diphenyl-3- pyridazinamine 2472-(4-(4-((4-((3-(2-amino-4-pyrimidinyl)- 0.0198 0.0042 0.3348 528 A12-pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenyl)ethanol 248N-(5-((3-(2-(methylamino)-4- 0.1488 0.0110 0.4647 499 A4pyrimidinyl)-2-pyridinyl)oxy)-2- pyridinyl)-4-phenyl-1-phthalazinamine249 (4-(4-((4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ ++ 514 A1pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenyl)methanol 250N-(4-((3-(2-amino-4-pyrimidinyl)-2- 0.0303 0.0199 0.175 474 A2pyridinyl)oxy)phenyl)-4-phenylfuro[2,3- d]pyridazin-7-amine 251N-(4-((3-(2-amino-4-pyrimidinyl)-2- 0.0160 0.0004 505 A1pyridinyl)oxy)phenyl)-4-(3-methyl-5- isothiazolyl)-1-phthalazinamine 2524-phenyl-N-(4-((2-(4- 0.1663 0.6600 467 A1pyridinyl)phenyl)oxy)phenyl)-1- phthalazinamine 253N-(4-((3-(2-amino-4-pyrimidinyl)-2- 2.3246 0.4724 544 A1pyridinyl)oxy)phenyl)-4-(2,6- bis(methyloxy)phenyl)-1-phthalazinamine254 N-(4-((2-(2-amino-4- +++ +++ 483 A1pyrimidinyl)phenyl)oxy)phenyl)-4- phenyl-1-phthalazinamine 255N-(3-(6-(methylamino)-4-pyrimidinyl)-2- ++ +++ 497 Cpyridinyl)-N′-(4-phenyl-1-phthalazinyl)- 1,4-benzenediamine 256(1R)-1-(4-(4-((4-((3-(2-amino-4- 0.1493 0.0018 528 A2 pyrimidinyl)-2-pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenyl)ethanol 257(1S)-1-(4-(4-((4-((3-(2-amino-4- +++ +++ 528 A2 pyrimidinyl)-2-pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenyl)ethanol 258N-(4-((3-(2-amino-4-pyrimidinyl)-2- + ++ 518 A2pyridinyl)oxy)phenyl)-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)- 1-phthalazinamine 259N-(4-((3-(2-amino-4-pyrimidinyl)-2- 0.0059 0.0028 0.0417 482 B1pyridinyl)oxy)phenyl)-4,5-dimethyl-6-(4-methyl-2-thienyl)-3-pyridazinamine 260N-(4-((3-(2-amino-4-pyrimidinyl)-2- 0.0330 0.0148 0.2281 483 B1pyridinyl)oxy)phenyl)-4-phenyl-1- isoquinolinamine 2614-phenyl-N-(4-((3-(4-pyridinyl)-2- ++ ++ + 469 A1pyrazinyl)oxy)phenyl)-1-phthalazinamine 262N-(4-((3-(2-amino-4-pyrimidinyl)-2- 0.0348 0.0158 0.3339 503 B1pyridinyl)oxy)phenyl)-4-(4-methyl-2- thienyl)-1-isoquinolinamine 2633-((4-((3-(2-amino-4-pyrimidinyl)-2- + + + 450 A2pyridinyl)oxy)phenyl)amino)-6-phenyl-4- pyridazinol 264N-(4-(3,4′-bipyridin-2-yloxy)phenyl)-5- + + 434 A2bromo-3-methyl-2-pyridinamine 265 N-(4-((3-(2-amino-4-pyrimidinyl)-2-+++ +++ 517 B1 pyridinyl)oxy)phenyl)-4-(4-chlorophenyl)-1-isoquinolinamine 266 N-(6-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 484B1 pyridinyl)oxy)-3-pyridinyl)-4-phenyl-1- isoquinolinamine 2674-phenyl-N-(6-((3-(2-((3-(1- 0.0964 0.0104 610 Dpiperidinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)-3-pyridinyl)-1- phthalazinamine 268N-(4-((3-(1H-imidazol-1-yl)-2- + + 457 A1pyridinyl)oxy)phenyl)-4-phenyl-1- phthalazinamine 269N-(6-((3-(2-amino-4-pyrimidinyl)-2- ++ +++ 451 A1pyridinyl)oxy)-3-pyridinyl)-4-(1- methylethyl)-1-phthalazinamine 270N-(6-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 500 A1pyridinyl)oxy)-3-pyridinyl)-4-(6-methyl- 2-pyridinyl)-1-phthalazinamine271 N-(4-((3-(2-amino-4-pyrimidinyl)-2- 0.0243 0.0010 499 A1pyridinyl)oxy)phenyl)-4-(6-methyl-2- pyridinyl)-1-phthalazinamine 272N-(4-((3-(2-amino-4-pyrimidinyl)-2- 0.0197 0.0055 490 A1pyridinyl)oxy)phenyl)-4-cyclohexyl-1- phthalazinamine 273N-(4-((3-(2-amino-4-pyrimidinyl)-2- ++ +++ 450 A1pyridinyl)oxy)phenyl)-4-(1-methylethyl)- 1-phthalazinamine 274N-(6-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ +++ 491 A1pyridinyl)oxy)-3-pyridinyl)-4-cyclohexyl- 1-phthalazinamine 275N-(4-((3-(2-((3-(4-methyl-1- 0.0949 0.0134 639 Dpiperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(6-methyl-2- pyridinyl)-1-phthalazinamine 2764-(6-methyl-2-pyridinyl)-N-(4-((3-(2-((3- ++ +++ 624 D(1-piperidinyl)propyl)amino)-4- pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1-phthalazinamine 277 4-(6-methyl-2-pyridinyl)-N-(4-((3-(2-((3- 0.12580.0027 625 D (1-piperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 278N-(4-((3-(2-amino-4-pyrimidinyl)-2- 0.0299 0.0074 0.2822 509 B4pyridinyl)oxy)phenyl)-4-(3-fluoro-1- piperidinyl)-1-phthalazinamine 279N-(3-(4-methyl-1-piperazinyl)propyl)-2- ++ +++ ++ 624 A1((4-((4-phenyl-1- phthalazinyl)amino)phenyl)oxy)-3,4′-bipyridin-2′-amine 280 4-methyl-N-(6-((3-(2-((3-(4-methyl-1- +++ +++ ++590 D piperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)-3-pyridinyl)-6-phenyl-3- pyridazinamine 2814-(2-((4-((4-phenyl-1- 0.0204 0.0061 0.1704 523 A1phthalazinyl)amino)phenyl)oxy)-3- pyridinyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one 282 4-(2-((4-((4-methyl-6-phenyl-3- +++ +++ ++ 487 A2pyridazinyl)amino)phenyl)oxy)-3- pyridinyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one 283 4-phenyl-N-(4-((3-(5,6,7,8-tetrahydro-1,8- + ++ 523A1 naphthyridin-4-yl)-2- pyridinyl)oxy)phenyl)-1-phthalazinamine 2844-(4-methyl-1,3-thiazol-2-yl)-N-(4-((3- 0.1670 0.1906 544 A1(5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)- 2-pyridinyl)oxy)phenyl)-1-phthalazinamine 285 4-methyl-6-phenyl-N-(4-((3-(5,6,7,8- + ++ 487 A2tetrahydro-1,8-naphthyridin-4-yl)-2-pyridinyl)oxy)phenyl)-3-pyridazinamine 2864-methyl-6-(4-methyl-1,3-thiazol-2-yl)-N- + 508 A2(4-((3-(5,6,7,8-tetrahydro-1,8- naphthyridin-4-yl)-2-pyridinyl)oxy)phenyl)-3-pyridazinamine 287N-(4-((3-(2,3-dihydro-1H-pyrrolo[2,3- 0.0833 0.0103 509 A1b]pyridin-4-yl)-2-pyridinyl)oxy)phenyl)- 4-phenyl-1-phthalazinamine 288N-(4-((3-(2,3-dihydro-1H-pyrrolol[2,3- +++ + 530 A2b]pyridin-4-yl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-1,3-thiazol-2-yl)-1- phthalazinamine 289N-(6-((3-(2-amino-4-pyrimidinyl)-2- 0.0241 0.0019 500 A1pyridinyl)oxy)-3-pyridinyl)-4-(5-methyl- 2-pyridinyl)-1-phthalazinamine290 N-(2-((2-(2-(((4- + 604 D (methyloxy)phenyl)methyl)amino)-4-pyridinyl)phenyl)oxy)-5-pyrimidinyl)-4- phenyl-1-phthalazinamine 291N-(4-((3-(5-fluoro-2-((3-(4-methyl-1- 0.0157 0.0030 642 Dpiperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenyl-1- phthalazinamine 292N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 515 A1pyridinyl)oxy)phenyl)-4-(6-(methyloxy)- 2-pyridinyl)-1-phthalazinamine293 N-(6-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 516 A1pyridinyl)oxy)-3-pyridinyl)-4-(6- (methyloxy)-2-pyridinyl)-1-phthalazinamine 294 N-(4-((3-(2-(1-azetidinyl)-4-pyrimidinyl)- +++ 524 D2-pyridinyl)oxy)phenyl)-4-phenyl-1- phthalazinamine 295N-(4-((3-(2-((3-(1- ++ +++ 581 Dazetidinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenyl-1- phthalazinamine 296(6-(4-((4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 557 A1pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)-2-pyridinyl)methyl acetate297 (6-(4-((4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 515 A1pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)-2-pyridinyl)methanol 298N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 530 A1pyridinyl)oxy)phenyl)-4-(6- ((methyloxy)methyl)-2-pyridinyl)-1-phthalazinamine 299 N-(4-((3-(2-amino-4-pyrimidinyl)-2- ++ +++ + 541 A2pyridinyl)oxy)phenyl)-4-(3- ((dimethylamino)methyl)phenyl)-1-phthalazinamine 300 N-(4-((3-(3-methyl-1H-pyrazol-4-yl)-2- ++ ++ ++ 471A1 pyridinyl)oxy)phenyl)-4-phenyl-1- phthalazinamine 301N-(4-((3-(3-amino-1H-pyrazol-4-yl)-2- 0.0055 0.0031 0.1664 486 A1pyridinyl)oxy)phenyl)-4-(4- methylphenyl)-1-phthalazinamine 302N-(4-((3-(3-amino-1H-pyrazol-4-yl)-2- +++ +++ + 436 A2pyridinyl)oxy)phenyl)-4-methyl-6-phenyl- 3-pyridazinamine 303N-(4-((3-(3-amino-1H-pyrazol-4-yl)-2- 0.0032 0.0166 0.7287 486 A1pyridinyl)oxy)phenyl)-4-(phenylmethyl)- 1-phthalazinamine 304N-(4-((3-(3-amino-1H-pyrazol-4-yl)-2- 0.0164 0.0687 0.7884 478 A1pyridinyl)oxy)phenyl)-4-phenylthieno[2,3- d]pyridazin-7-amine 305(3-(4-((4-((3-(3-amino-1H-pyrazol-4-yl)- +++ +++ + 502 A12-pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenyl)methanol 306N-(4-((3-(3-amino-1H-pyrazol-4-yl)-2- +++ +++ ++ 506 A1pyridinyl)oxy)phenyl)-4-(4-chlorophenyl)- 1-phthalazinamine 307N-(4-((3-(3-amino-1H-pyrazol-4-yl)-2- +++ +++ ++ 492 A1pyridinyl)oxy)phenyl)-4-(4-methyl-2- thienyl)-1-phthalazinamine 308N-(4-((3-(3-amino-1H-pyrazol-4-yl)-2- +++ +++ + 476 A2pyridinyl)oxy)phenyl)-4-phenyl-5,6,7,8- tetrahydro-1-phthalazinamine 309N-(4-((3-(3-amino-1H-pyrazol-4-yl)-2- +++ +++ + 493 A1pyridinyl)oxy)phenyl)-4-(4-methyl-1,3- thiazol-2-yl)-1-phthalazinamine310 N-(4-((3-(2-(hydroxyamino)-4- +++ +++ 500 A1pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4- phenyl-1-phthalazinamine 311N-(5-(3,4′-bipyridin-2-yloxy)-2- + + 470 A3pyrimidinyl)-4-phenyl-1-phthalazinamine 312N-(4-((3-(3-amino-1H-pyrazol-4-yl)-2- +++ +++ 511 A1pyridinyl)oxy)-3-fluorophenyl)-4-(4- methyl-1,3-thiazol-2-yl)-1-phthalazinamine 313 N-(6-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 491 A1pyridinyl)oxy)-3-pyridinyl)-4- phenylthieno[2,3-d]pyridazin-7-amine 314N-(4-((3-(3-amino-1H-pyrazol-4-yl)-2- 0.0045 0.0024 490 A1pyridinyl)oxy)-3-fluorophenyl)-4-phenyl- 1-phthalazinamine 315N-(6-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 519 A1pyridinyl)oxy)-3-pyridinyl)-4-(4- chlorophenyl)-1-phthalazinamine 316N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 562 A1pyridinyl)oxy)phenyl)-4-(3- (methylsulfonyl)phenyl)-1- phthalazinamine317 N-(4-((3-(3-amino-1H-pyrazol-4-yl)-2- +++ +++ 502 A1pyridinyl)oxy)phenyl)-4-(3- (methyloxy)phenyl)-1-phthalazinamine 318N-(6-((3-(2-amino-4-pyrimidinyl)-2- 0.0238 0.0056 563 A1pyridinyl)oxy)-3-pyridinyl)-4-(3- (methylsulfonyl)phenyl)-1-phthalazinamine 319 N-(6-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 515 A1pyridinyl)oxy)-3-pyridinyl)-4-(4- (methyloxy)phenyl)-1-phthalazinamine320 N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 514 A1pyridinyl)oxy)phenyl)-4-(4- (methyloxy)phenyl)-1-phthalazinamine 321N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 528 A1pyridinyl)oxy)phenyl)-4-(4- (ethyloxy)phenyl)-1-phthalazinamine 322N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 528 A1pyridinyl)oxy)phenyl)-4-(2- (ethyloxy)phenyl)-1-phthalazinamine 323N-(4-((3-(2-((3-(4-methyl-1- ++ +++ 625 Dpiperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(2-pyridinyl)- 1-phthalazinamine 324N-(4-((3-(2-((3-(3-(dimethylamino)-1- +++ +++ 638 Dpyrrolidinyl)propyl)amino)-4- pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine 325 4-(2-((4-((4-phenyl-1- + 485 Dphthalazinyl)amino)phenyl)oxy)-3- pyridinyl)-2-pyrimidinol 326N-(4-((3-(2-((3-(2,6-dimethyl-4- +++ +++ 639 Dmorpholinyl)propyl)amino)-4- pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine 327 N-(4-(2-((4-((4-phenyl-1- ++ + 556 Dphthalazinyl)amino)phenyl)oxy)-3- pyridinyl)-2-pyrimidinyl)-beta-alanine328 N-(4-((3-(2-((3-((2S,5S)-2,5-dimethyl-4- 0.0650 0.0043 639 Dmorpholinyl)propyl)amino)-4- pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine 329 1-(3-(4-((4-((3-(2-amino-4-pyrimidinyl)-2-526 A1 pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenyl)ethanone 330N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ +++ 505 A1pyridinyl)oxy)phenyl)-4-(4-methyl-1,3- thiazol-2-yl)-1-phthalazinamine331 N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ +++ 504 A1pyridinyl)oxy)phenyl)-4-(4-methyl-2- thienyl)-1-phthalazinamine 332N-(6-((3-(2-amino-4-pyrimidinyl)-2- 0.0052 0.0016 0.0033 505 B1pyridinyl)oxy)-3-pyridinyl)-4-(4-methyl- 2-thienyl)-1-phthalazinamine333 N-(4-((3-(2-((3-(4-methyl-1- +++ +++ +++ 624 Dpiperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenyl-1- phthalazinamine 334N-(4-((3-(2-amino-4-pyrimidinyl)-2- ++ +++ + 455 A2pyridinyl)oxy)phenyl)-4-methyl-6-(1- piperidinyl)-3-pyridazinamine 3354-phenyl-N-(4-((3-(2-((4- + ++ + 581 Dpiperidinylmethyl)amino)-4-pyrimidinyl)- 2-pyridinyl)oxy)phenyl)-1-phthalazinamine 336 N-(4-((3-(2-amino-4-pyrimidinyl)-2- + ++ + 541 Epyridinyl)oxy)phenyl)-4-(4- ((dimethylamino)methyl)phenyl)-1-phthalazinamine 337 3-((4-(2-((4-((4-phenyl-1- +++ +++ ++ 558 Dphthalazinyl)amino)phenyl)oxy)-3- pyridinyl)-2-pyrimidinyl)amino)-1,2-propanediol 338 N,N-dimethyl-N′-(4-(2-((4-((4-phenyl-1- +++ +++ +++ 583D phthalazinyl)amino)phenyl)oxy)-3- pyridinyl)-2-pyrimidinyl)-1,4-butanediamine 339 3-((4-(2-((4-((4-phenyl-1- +++ +++ ++ 542 Dphthalazinyl)amino)phenyl)oxy)-3- pyridinyl)-2-pyrimidinyl)amino)-1-propanol 340 4-phenyl-N-(4-((3-(2-((3-(1- +++ +++ ++ 610 Dpiperazinyl)propyl)amino)-4-pyrimidinyl)- 2-pyridinyl)oxy)phenyl)-1-phthalazinamine 341 2,2′-((3-((4-(2-((4-((4-phenyl-1- ++ +++ ++ 629 Dphthalazinyl)amino)phenyl)oxy)-3- pyridinyl)-2-pyrimidinyl)amino)propyl)imino)diethanol 342(3-(4-((4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ ++ 514 A1pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenyl)methanol 3433-(4-((4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ +++ 500 A1pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenol 3443-(3-(4-((4-((3-(2-amino-4-pyrimidinyl)- +++ +++ +++ 542 A12-pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenyl)-1-propanol 3452-((4-((4-(4-methyl-1,3-thiazol-2-yl)-1- +++ +++ ++ 504 A1phthalazinyl)amino)phenyl)oxy)-3,4′- bipyridin-2′-amine 3461-(3-(4-((4-((3-(2-amino-4-pyrimidinyl)- +++ +++ ++ 528 A12-pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenyl)ethanol 3472-(ethyl(4-((4-(2-((4-((4-phenyl-1- +++ +++ +++ 627 Dphthalazinyl)amino)phenyl)oxy)-3- pyridinyl)-2-pyrimidinyl)amino)butyl)amino)ethanol 3482-(ethyl(4-((4-(2-((4-((4-methyl-6-phenyl- +++ +++ ++ 591 D3-pyridazinyl)amino)phenyl)oxy)-3- pyridinyl)-2-pyrimidinyl)amino)butyl)amino)ethanol 3492-(ethyl(3-((4-(2-((4-((4-phenyl-1- ++ +++ ++ 613 Dphthalazinyl)amino)phenyl)oxy)-3- pyridinyl)-2-pyrimidinyl)amino)propyl)amino)ethanol 3502-(ethyl(3-((4-(2-((4-((4-methyl-6-phenyl- +++ +++ ++ 577 D3-pyridazinyl)amino)phenyl)oxy)-3- pyridinyl)-2-pyrimidinyl)amino)propyl)amino)ethanol 351(3-(4-((4-((3-(2-amino-4-pyrimidinyl)-2- ++ +++ 594 Fpyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenyl)methyl dihydrogenphosphate 352 (1-(4-((4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 521 A2pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)-3-piperidinyl)methanol 353(1-(4-((4-((3-(2-amino-4-pyrimidinyl)-2- +++ 521 A2pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)-4-piperidinyl)methanol 3541-(4-((4-((3-(2-amino-4-pyrimidinyl)-2- 0.0874 0.0259 507 A2pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)-3-piperidinol 3552-(3-(4-((4-((3-(2-amino-4-pyrimidinyl)- +++ +++ 528 A12-pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenyl)ethanol 356N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 485 A1pyridinyl)oxy)phenyl)-4-(2-pyridinyl)-1- phthalazinamine 3572-(3-(4-((4-((3-(2-amino-4-pyrimidinyl)- +++ +++ 542 A12-pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenyl)-2-propanol 3581-(4-((4-((3-(2-amino-4-pyrimidinyl)-2- + +++ 507 A1pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)-4-piperidinol 3593-((4-(2-((4-((4-(4-methyl-1,3-thiazol-2- +++ +++ 563 A1yl)-1-phthalazinyl)amino)phenyl)oxy)-3-pyridinyl)-2-pyrimidinyl)amino)-1- propanol 360(1S)-1-(3-(4-((4-((3-(2-amino-4- +++ +++ 528 A2 pyrimidinyl)-2-pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenyl)ethanol 361(1R)-1-(3-(4-((4-((3-(2-amino-4- +++ +++ 528 A1 pyrimidinyl)-2-pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenyl)ethanol 3623-(3-(4-((4-((3-(2-amino-4-pyrimidinyl)- +++ +++ 622 F2-pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenyl)propyl dihydrogenphosphate 363 3-(4-((6-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 501 A1pyridinyl)oxy)-3-pyridinyl)amino)-1- phthalazinyl)phenol 3642-(4-((4-((3-(2-amino-4-pyrimidinyl)-2- ++ +++ 500 A1pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenol 3652-(4-((6-((3-(2-amino-4-pyrimidinyl)-2- 0.0276 0.0113 501 A1pyridinyl)oxy)-3-pyridinyl)amino)-1- phthalazinyl)phenol 3663-(4-((4-((3-(2-amino-4-pyrimidinyl)-2- ++ ++ 580 Fpyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenyl dihydrogen phosphate367 3-((4-(2-((5-((4-phenyl-1- +++ +++ 543 A1phthalazinyl)amino)-2-pyridinyl)oxy)-3-pyridinyl)-2-pyrimidinyl)amino)-1- propanol 3682-(4-((4-((3-(2-amino-4-pyrimidinyl)-2- + + 580 Fpyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenyl dihydrogen phosphate369 (1S)-1-(3-(4-((6-((3-(2-amino-4- +++ +++ 529 A2pyrimidinyl)-2-pyridinyl)oxy)-3- pyridinyl)amino)-1-phthalazinyl)phenyl)ethanol 370 (3-(6-((4-((3-(2-amino-4-pyrimidinyl)-2-+++ +++ 478 A2 pyridinyl)oxy)phenyl)amino)-5-methyl-3-pyridazinyl)phenyl)methanol 371 2-(4-((4-((2′-amino-3,4′-bipyridin-2- +++++ 499 A1 yl)oxy)phenyl)amino)-1- phthalazinyl)phenol 372N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 532 A1pyridinyl)oxy)phenyl)-4-(2-fluoro-5-(methyloxy)phenyl)-1-phthalazinamine 3733-(4-((4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 518 A1pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)-4-fluorophenol 374N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 585 A2pyridinyl)oxy)phenyl)-4-(3-((3- (dimethylamino)propyl)oxy)phenyl)-1-phthalazinamine 375 (3-(4-((6-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 515A1 pyridinyl)oxy)-3-pyridinyl)amino)-1- phthalazinyl)phenyl)methanol 376N-(6-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 533 A1pyridinyl)oxy)-3-pyridinyl)-4-(2-fluoro-5-(methyloxy)phenyl)-1-phthalazinamine 377N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 568 A1pyridinyl)oxy)phenyl)-4-(3- ((trifluoromethyl)oxy)phenyl)-1-phthalazinamine 378 N-(6-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 569 A1pyridinyl)oxy)-3-pyridinyl)-4-(3- ((trifluoromethyl)oxy)phenyl)-1-phthalazinamine 379 3-(4-((6-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 519A1 pyridinyl)oxy)-3-pyridinyl)amino)-1- phthalazinyl)-4-fluorophenol 380N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 532 A1pyridinyl)oxy)phenyl)-4-(5-fluoro-2-(methyloxy)phenyl)-1-phthalazinamine 381N-(6-((3-(2-amino-4-pyrimidinyl)-2- ++ +++ 533 A1pyridinyl)oxy)-3-pyridinyl)-4-(5-fluoro-2-(methyloxy)phenyl)-1-phthalazinamine 382N-(4-((3-(2-amino-4-pyrimidinyl)-2- ++ +++ 568 A1pyridinyl)oxy)phenyl)-4-(2- ((trifluoromethyl)oxy)phenyl)-1-phthalazinamine 383 N-(6-((3-(2-amino-4-pyrimidinyl)-2- + +++ 569 A1pyridinyl)oxy)-3-pyridinyl)-4-(2- ((trifluoromethyl)oxy)phenyl)-1-phthalazinamine 384 (2-(4-((4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 514A1 pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)phenyl)methanol 385(2-(4-((6-((3-(2-amino-4-pyrimidinyl)-2- ++ +++ 515 A1pyridinyl)oxy)-3-pyridinyl)amino)-1- phthalazinyl)phenyl)methanol 3862-(4-((4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 518 A1pyridinyl)oxy)phenyl)amino)-1- phthalazinyl)-4-fluorophenol 3872-(4-((6-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 519 A1pyridinyl)oxy)-3-pyridinyl)amino)-1- phthalazinyl)-4-fluorophenol 388N-(6-((3-(2-amino-4-pyrimidinyl)-2- ++ +++ 586 A2pyridinyl)oxy)-3-pyridinyl)-4-(3-((3-(dimethylamino)propyl)oxy)phenyl)-1- phthalazinamine 389N-(6-((3-(2-((3-(4-methyl-1- +++ +++ 625 Dpiperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)-3-pyridinyl)-4-phenyl-1- phthalazinamine 3904-phenyl-N-(6-((3-(2-((3-(1- +++ +++ 611 Dpiperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)-3-pyridinyl)-1- phthalazinamine 3912-(4-((6-((3-(2-amino-4-pyrimidinyl)-2- 1.5953 0.6409 581 Fpyridinyl)oxy)-3-pyridinyl)amino)-1- phthalazinyl)phenyl dihydrogenphosphate 392 3-(4-((6-((3-(2-amino-4-pyrimidinyl)-2- + + 581 Fpyridinyl)oxy)-3-pyridinyl)amino)-1- phthalazinyl)phenyl dihydrogenphosphate 393 N-(4-((3-(2-amino-4-pyrimidinyl)-2- + ++ 492 B4pyridinyl)oxy)phenyl)-4-(1-piperazinyl)- 1-phthalazinamine 394N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 532 B4pyridinyl)oxy)phenyl)-4- (hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-1-phthalazinamine 395 N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++520 B4 pyridinyl)oxy)phenyl)-4-(3,4-dimethyl-1-piperazinyl)-1-phthalazinamine 396 N-(4-((3-(2-amino-4-pyrimidinyl)-2-0.0047 0.0008 499 A1 pyridinyl)oxy)phenyl)-4-(5-methyl-2-pyridinyl)-1-phthalazinamine 397 N-(6-((3-(2-amino-4-pyrimidinyl)-2- ++++++ 533 B4 pyridinyl)oxy)-3-pyridinyl)-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)- yl)-1-phthalazinamine 398N-(4-((3-(2-amino-4-pyrimidinyl)-2- ++ 506 B4pyridinyl)oxy)phenyl)-4-((3S)-3-methyl- 1-piperazinyl)-1-phthalazinamine399 N-(4-((3-(2-amino-4-pyrimidinyl)-2- + ++ 506 B4pyridinyl)oxy)phenyl)-4-((3R)-3-methyl- 1-piperazinyl)-1-phthalazinamine400 N-(4-((3-(5-fluoro-2-((3-(1- ++ +++ 628 Dpiperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenyl-1- phthalazinamine 401N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 532 B4pyridinyl)oxy)phenyl)-4-((8aS)- hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-1-phthalazinamine 402 N-(6-((3-(2-amino-4-pyrimidinyl)-2- +++ +++533 B4 pyridinyl)oxy)-3-pyridinyl)-4-((8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)- yl)-1-phthalazinamine 403N-(4-((3-(5-fluoro-2-((3-(1- +++ +++ 627 Dpiperidinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenyl-1- phthalazinamine 404N-(4-((3-(2-amino-4-pyrimidinyl)-2- ++ +++ 499 A1pyridinyl)oxy)phenyl)-4-(4-methyl-2- pyridinyl)-1-phthalazinamine 405N-(6-((3-(2-amino-4-pyrimidinyl)-2- ++ +++ 500 A1pyridinyl)oxy)-3-pyridinyl)-4-(4-methyl- 2-pyridinyl)-1-phthalazinamine406 N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 546 B4pyridinyl)oxy)phenyl)-4-(octahydro-2H- pyrido[1,2-a]pyrazin-2-yl)-1-phthalazinamine 407 N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 488 B7pyridinyl)oxy)phenyl)-4-(5-methyl-1H- pyrazol-1-yl)-1-phthalazinamine408 N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 488 B7pyridinyl)oxy)phenyl)-4-(3-methyl-1H- pyrazol-1-yl)-1-phthalazinamine409 N-(4-((3-(2-((3-(4-methyl-1- ++ +++ 639 Dpiperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2- pyridinyl)-1-phthalazinamine 4104-(6-(methyloxy)-2-pyridinyl)-N-(4-((3- +++ +++ 655 D(2-((3-(4-methyl-1- piperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 411N-(4-((3-(2-((3-((3S)-3-methyl-1- +++ +++ 624 Dpiperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenyl-1- phthalazinamine 4124-(4-methyl-2-pyridinyl)-N-(4-((3-(2-((3- ++ +++ 626 D(4-morpholinyl)propyl)amino)-4- pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1-phthalazinamine 413 2-(((3-(4-((4-((3-(2-amino-4-pyrimidinyl)- +++ 557A2 2-pyridinyl)oxy)phenyl)amino)-1-phthalazinyl)phenyl)methyl)amino)ethanol 414N-(6-((3-(2-amino-4-pyrimidinyl)-2- 506 A1pyridinyl)oxy)-3-pyridinyl)-4-(3-methyl-5-isothiazolyl)-1-phthalazinamine 415 N-(6-((3-(2-amino-4-pyrimidinyl)-2-+++ +++ +++ 486 A1 pyridinyl)oxy)-3-pyridinyl)-4-phenyl-1-phthalazinamine 416 2-((4-((4-(4-methyl-2-thienyl)-1- 0.0541 0.01450.1338 504 A1 phthalazinyl)amino)phenyl)oxy)-3,4′- bipyridin-2′-amine417 N-(4-(3,4′-bipyridin-2-yloxy)phenyl)-4- +++ +++ + 432 A2methyl-6-phenyl-3-pyridazinamine 418 2-((4-((4-methyl-6-phenyl-3- ++++++ ++ 448 A2 pyridazinyl)amino)phenyl)oxy)-3,4′- bipyridin-2′-amine 4192-((4-((4-methyl-6-(4-methyl-2-thienyl)-3- +++ +++ ++ 468 A2pyridazinyl)amino)phenyl)oxy)-3,4′- bipyridin-2′-amine 4202-((4-((4-ethyl-6-phenyl-3- 0.0568 0.0071 0.3140 462 A2pyridazinyl)amino)phenyl)oxy)-3,4′- bipyridin-2′-amine 4213-((4-(2-((4-((4-phenyl-1- ++ ++ + 607 Dphthalazinyl)amino)phenyl)oxy)-3- pyridinyl)-2-pyrimidinyl)amino)-1-propanesulfonic acid 422 4-methyl-N-(4-((3-(2-((3-(4-methyl-1- +++ +++++ 589 D piperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-6-phenyl-3- pyridazinamine 423N,N-dimethyl-N′-(4-(2-((4-((4-methyl-6- +++ +++ ++ 548 Dphenyl-3-pyridazinyl)amino)phenyl)oxy)- 3-pyridinyl)-2-pyrimidinyl)-1,4-butanediamine 424 4-methyl-6-phenyl-N-(4-((3-(2-((3-(1- +++ +++ ++ 574 Dpiperidinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-3-pyridazinamine 4254-methyl-6-phenyl-N-(4-((3-(2-((3-(1- +++ +++ ++ 560 Dpyrrolidinyl)propyl)amino)-4- pyrimidinyl)-2-pyridinyl)oxy)phenyl)-3-pyridazinamine 426 N,N-diethyl-N′-(4-(2-((4-((4-methyl-6- +++ +++ ++ 562D phenyl-3-pyridazinyl)amino)phenyl)oxy)-3-pyridinyl)-2-pyrimidinyl)-1,3- propanediamine 4274-((4-(2-((4-((4-phenyl-1- +++ +++ + 571 Dphthalazinyl)amino)phenyl)oxy)-3-pyridinyl)-2-pyrimidinyl)amino)butanoic acid 428N-(4-(3,4′-bipyridin-2-yloxy)phenyl)-4- +++ +++ + 453 A2methyl-6-(4-methyl-2-thienyl)-3- pyridazinamine 4293-((4-(2-((4-((4-methyl-6-phenyl-3- +++ +++ ++ 507 Dpyridazinyl)amino)phenyl)oxy)-3- pyridinyl)-2-pyrimidinyl)amino)-1-propanol 430 4-((4-(2-((4-((4-methyl-6-phenyl-3- +++ +++ + 535 Dpyridazinyl)amino)phenyl)oxy)-3- pyridinyl)-2-pyrimidinyl)amino)butanoicacid 431 2-((5-((4-phenyl-1-phthalazinyl)amino)-2- +++ +++ +++ 485 A1pyridinyl)oxy)-3,4′-bipyridin-2′-amine 432 2-((4-((4-phenyl-1- + + 485A1 phthalazinyl)amino)phenyl)oxy)-3,4′- bipyridin-2′(1′H)-one 4333-((4-((3-(2-amino-4-pyrimidinyl)-2- + + + 478 A1pyridinyl)oxy)phenyl)amino)-6-phenyl-4- pyridazinecarboxylic acid 4342-((4-((4-methyl-6-(4-methyl-1,3-thiazol- 0.0986 0.0095 1.000 469 A22-yl)-3-pyridazinyl)amino)phenyl)oxy)- 3,4′-bipyridin-2′-amine 435N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 463 Cpyridinyl)oxy)phenyl)-4-ethyl-6-phenyl-3- pyridazinamine 4362-((4-((4-phenyl-1- ++ +++ 493 A1 phthalazinyl)amino)phenyl)oxy)-3-(4-pyridinyl)benzonitrile 437 N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++515 A1 pyridinyl)oxy)phenyl)-4-(2- (methyloxy)phenyl)-1-phthalazinamine438 N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 515 A1pyridinyl)oxy)phenyl)-4-(3- (methyloxy)phenyl)-1-phthalazinamine 439N-(6-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 464 Cpyridinyl)oxy)-3-pyridinyl)-4-ethyl-6- phenyl-3-pyridazinamine 440N-(6-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 516 A1pyridinyl)oxy)-3-pyridinyl)-4-(2- (methyloxy)phenyl)-1-phthalazinamine441 2-((4-((4-(3-(methyloxy)phenyl)-1- ++ ++ 514 A1phthalazinyl)amino)phenyl)oxy)-3,4′- bipyridin-2′-amine 4422-((4-((4-(2-(methyloxy)phenyl)-1- 0.3748 0.0330 514 A1phthalazinyl)amino)phenyl)oxy)-3,4′- bipyridin-2′-amine 443N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 479 A2pyridinyl)oxy)phenyl)-4-methyl-6-(3- (methyloxy)phenyl)-3-pyridazinamine444 2-((5-((4-ethyl-6-phenyl-3- ++ +++ 463 Cpyridazinyl)amino)-2-pyridinyl)oxy)-3,4′- bipyridin-2′-amine 445N-(4-((3-(2-amino-4-pyrimidinyl)-2- 0.0235 0.0031 477 A2pyridinyl)oxy)phenyl)-6-phenyl-4-propyl- 3-pyridazinamine 446N-(4-((3-(2-amino-4-pyrimidinyl)-2- +++ +++ 479 A2pyridinyl)oxy)phenyl)-4- ((methyloxy)methyl)-6-phenyl-3- pyridazinamine447 2-((4-((4-phenyl-1- + 484 A1 phthalazinyl)amino)phenyl)oxy)-3-(4-pyridinyl)phenol 448 N-(4-((2-(methyloxy)-6-(4- 0.1101 0.0096 498 A1pyridinyl)phenyl)oxy)phenyl)-4-phenyl-1- phthalazinamine 4494-ethyl-N-(6-((3-(2-((3-(4-methyl-1- +++ +++ 604 Dpiperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)-3-pyridinyl)-6-phenyl-3- pyridazinamine 4504-ethyl-6-phenyl-N-(6-((3-(2-((3-(1- + +++ 589 Dpiperidinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)-3-pyridinyl)-3- pyridazinamine 4514-ethyl-6-phenyl-N-(6-((3-(2-((3-(1- ++ +++ 590 Dpiperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)-3-pyridinyl)-3- pyridazinamine 452N-(4-((3-(2-((3-(3-fluoro-1- +++ +++ 628 Dpiperidinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenyl-1- phthalazinamine 453N-(4-((3-(2-((3-(3,3-difluoro-1- +++ +++ 646 Dpiperidinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenyl-1- phthalazinamine 4544-(6-(methyloxy)-2-pyridinyl)-N-(4-((3- +++ +++ 641 D(2-((3-(1-piperidinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 4554-(6-(methyloxy)-2-pyridinyl)-N-(4-((3- +++ +++ 627 D(2-((3-(1-pyrrolidinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine 4564-ethyl-N-(4-((3-(2-((3-(4-methyl-1- +++ +++ 603 Dpiperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-6-phenyl-3- pyridazinamine 4574-ethyl-6-phenyl-N-(4-((3-(2-((3-(1- +++ +++ 589 Dpiperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-3-pyridazinamine 4584-ethyl-6-phenyl-N-(4-((3-(2-((3-(1- +++ +++ 588 Dpiperidinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-3-pyridazinamine 4594-ethyl-6-phenyl-N-(4-((3-(2-((3-(1- ++ +++ 574 Dpyrrolidinyl)propyl)amino)-4- pyrimidinyl)-2-pyridinyl)oxy)phenyl)-3-pyridazinamine 460 4-(6-(methyloxy)-2-pyridinyl)-N-(4-((3- +++ +++ 642 D(2-((3-(1-piperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1- phthalazinamine

Preparations of the following additional intermediates and compounds offormulas I-III should further assist in appreciating the scope of thepresent invention.

Example 461

Synthesis of4-(2-(6-aminopyridin-3-yloxy)pyridin-3-yl)-N-methylpyrimidin-2-amineStep 1. Synthesis of4-(2-(6-bromopyridin-3-yloxy)pyridin-3-yl)-N-methylpyrimidin-2-amine

To a slurry of cesium carbonate (8.9 g, 27 mmol) and 6-bromopyridin-3-ol(2.6 g, 15 mmol) was added4-(2-chloropyridin-3-yl)-N-methylpyrimidin-2-amine (3.0 g, 14 mmol). Thereaction mixture was sealed and heated to 125° C. for 16 h. The mixturewas cooled and diluted with water and the aqueous solution was extractedwith DCM (3×75 mL). The combined organics were dried over anhydroussodium sulfate, filtered, and concentrated in vacuo to give a brown oil,which was taken up in a little DCM and purified on an ISCO 120 g column,eluting with a gradient of 0-100% EtOAc/DCM, to afford4-(2-(6-bromopyridin-3-yloxy)pyridin-3-yl)-N-methylpyrimidin-2-amine asan off-white solid. MS m/z=295 [M+H]⁺. Calc'd for C₁₅H₁₂BrN₅O: 358.2.

Step 2.4-(2-(6-Aminopyridin-3-yloxy)pyridin-3-yl)-N-methylpyrimidin-2-amine

The title compound was prepared following the procedure described inTet. Let. 2001 42, 3251-3254. A slurry of4-(2-(6-bromopyridin-3-yloxy)pyridin-3-yl)-N-methylpyrimidin-2-amine(2.42 g, 6.76 mmol) and copper(i) oxide (0.145 g, 1.01 mmol) in 35 mLethylene glycol in a 25 mL stainless steel pressure vessel with stir barwas cooled to 0° C., and anhydrous ammonia was bubbled through for 15min. The heterogeneous, reddish mixture was sealed, and heated to 100°C. in an oil bath overnight. The reaction was cooled to ambient temp andvented. The reaction was partitioned between water and DCM. The aqueouslayer was extracted 4× with DCM. The combined organics were dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2g of a light yellow solid. This was further purified by adsorbing onto10 g silica gel from MeOH/MC and purifying by silica gel chromatography,ISCO, 120 g, 40 min run, 0-70% 90/10 MC/MeOH in MC to provide4-(2-(6-aminopyridin-3-yloxy)pyridin-3-yl)-N-methylpyrimidin-2-amine asa white solid. MS m/z=295 [M+H]⁺. Calc'd for C₁₅H₁₄N₆O: 294.3.

Example 462

Synthesis of 4-(2-(4-aminophenoxy)phenyl)pyrimidin-2-amine Step 1.Preparation of4,4,5,5-tetramethyl-2-(2-(4-nitrophenoxy)phenyl)-1,3,2-dioxaborolane

To a solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol(2.00 g, 9.09 mmol) in DMF was added potassium carbonate (2.51 g, 18.2mmol) and 1-fluoro-4-nitrobenzene (0.964 ml, 9.09 mmol). The reactionmixture was flushed with nitrogen, sealed, and heated to 120° C. After18 h, water was added and the mixture was extracted 2× with EtOAc. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated invacuo, and the crude was purify by silica gel chromatography, elutingwith 0-15% EtOAc/hexanes to give4,4,5,5-tetramethyl-2-(2-(4-nitrophenoxy)phenyl)-1,3,2-dioxaborolane asa white solid. MS m/z=342 [M+1]⁺. Calc'd for C₁₈H₂₀BNO₅: 341.17.

Step 2. Preparation of 4-(2-(4-nitrophenoxy)phenyl)pyrimidin-2-amine

The compound of step 1 (0.034 g, 0.054 mmol), potassium acetate (0.26 g,2.7 mmol),4,4,5,5-tetramethyl-2-(2-(4-nitrophenoxy)phenyl)-1,3,2-dioxaborolane(0.460 g, 1.3 mmol), and 4-chloropyrimidin-2-amine (0.17 g, 1.3 mmol)were combined in a sealed tube under nitrogen, to which 7 mL ACN andwater (0.73 ml, 40 mmol) were added. The reaction was sealed and heatedto 85° C. overnight. The reaction was diluted with DCM and water, andextracted 2× with DCM. The combined organics were dried over anhydroussodium sulfate, filtered, and concentrated in vacuo. The resultingmaterial was purified by silica gel chromatography (MeOH/DCM) to give4-(2-(4-nitrophenoxy)phenyl)pyrimidin-2-amine as a white solid MSm/z=309 [M+H]⁺. Calc'd for C₁₆H₁₂N₄O₃: 308.3.

Step 3. Preparation of 4-(2-(4-aminophenoxy)phenyl)pyrimidin-2-amine

4-(2-(4-nitrophenoxy)phenyl)pyrimidin-2-amine (0.280 g, 0.908 mmol) andpalladium, 10 wt. % (dry basis) on activated carbon 50% water wet (0.193g, 0.182 mmol) were combined under nitrogen and diluted with 5 mL MeOH.The atmosphere was replaced with hydrogen, and the mixture was stiffedrapidly overnight. The reaction was flushed with nitrogen and wasfiltered through celite, rinsing with MeOH. Concentration in vacuoafforded 4-(2-(4-aminophenoxy)phenyl)pyrimidin-2-amine MS m/z=279[M+H]⁺. Calc'd for C₁₆H₁₄N₄O: 278.3.

Example 463

Synthesis of tert-Butyl4-(2-(4-aminophenoxy)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

In an argon-purged sealed tube, tert-butyl4-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (2.77 g, 11.0 mmol),4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)benzenamine(5.14 g, 16.5 mmol), sodium carbonate (3.49 g, 32.9 mmol), 1,4-dioxane(32.3 ml, 11.0 mmol), and water (11.7 ml, 11.0 mmol) were added. Thetube was sealed, and the reaction was stirred at RT for 5 min. Palladiumacetate (0.246 g, 1.10 mmol) and tri-t-butylphosphoniumtetrafluororoborate (0.637 g, 2.19 mmol) were added, and the tube wassealed and heated to 100° C. After ˜105 min, heating was stopped, thereaction mixture was cooled to RT and passed through a pad of celitewith an aid of EtOAc. The filtrate was dried over MgSO₄, filtered, andconcentrated. The crude product was purified by column chromatography on120 g silica gel column using DCM and 95:05 DCM:(90:10:1 DCM:MeOH:NH₄OH)to flush out the nonpolar spots, then 80:20 DCM:(90:10:1 DCM:MeOH:NH₄OH)to collect the Boc-product. A viscous brown oil was obtained. Aftersetting the oil at RT for several hours, crystals were formed. The oilwas cooled to 0° C. and light yellow solid precipitated out after addingsmall amounts of hexanes and a little bit of ether in addition toscratching the wall of the flash with a spatula. The light yellow solidwas filtered, washed with cold hexanes, and dried under vacuum. Thissolid, tert-butyl4-(2-(4-aminophenoxy)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylatewas mainly the product according to ¹H NMR. MS Calcd for C₂₃H₂₂N₄O₃:[M]⁺=402. Found: [M+H]⁺=403.

Example 464 Synthesis of3-(4-chlorophthalazin-1-yl)-N,N-dimethylprop-2-yn-1-amine

A resealable pressure bottle was charged withdichlorobis(triphenyl-phosphine)palladium(II) (106 mg, 0.15 mmol),N,N-dimethylprop-2-yn-1-amine (0.13 ml, 1.5 mmol),1,4-dichlorophthalazine (300 mg, 1.5 mmol), copper(I) iodide (29 mg,0.15 mmol), TEA (4.2 mL, 30.1 mmol), and ACN (15.0 mL, 0.1M). The vesselwas sealed and the mixture was stirred at overnight at 90° C. Next daythe reaction was cooled to RT, filtered over celite, and the filtratewas concentrated under reduced pressure to afford a brown residue, whichwas purified by ISCO silica gel chromatography (5%-7% of 90/10/1DCM/MeOH/NH₄OH to afford3-(4-chlorophthalazin-1-yl)-N,N-dimethylprop-2-yn-1-amine. MS m/z=246[M+1]⁺. Calc'd for C₁₃H₁₂ClN₃: 245.7.

Example 465 Synthesis of 1-(4-chlorophthalazin-1-yl)piperidin-3-ol

A resealable pressure bottle was charged with potassium carbonate (273mg, 2.0 mmol), 1,4-dichlorophthalazine (590 mg, 3.0 mmol),piperidin-3-ol (200 mg, 2.0 mmol) and methylsulfinylmethane (10 mL,0.2M). The vessel was sealed and the mixture stirred at 90° C. for 24hrs. Next day the reaction was cooled to RT and diluted with 5 ml ofDMSO. The solution was purified by Gilson reverse phase liquidchromatography (10% to 90% CH₃CN/H₂O/0.1% TFA) to afford1-(4-chlorophthalazin-1-yl)piperidin-3-ol. MS m/z=264 [M+1]⁺. Calculatedfor C₁₃H₁₄ClN₃O: 263.7.

Example 466 Synthesis of 1-chloro-4-(4-methylthiazol-2-yl)phthalazineStep 1: Preparation of 2-(4-methylthiazole-2-carbonyl)benzoic acid

A dry 250 mL RBF under nitrogen was charged with THF (35.3 mL, 0.4 M),and cooled to −78° C., via dry ice bath in acetone. n-Butyllithium (6.3mL, 15.8 mmol) was added via syringe. While keeping reaction mixture at−78° C., 4-methylthiazole (1.4 g, 15.1 mmol) in 40 mL of THF was addedvia addition funnel over 15 minutes. The reaction mixture was stirred at−78° C. for 2 hrs, allowed to warm up to 0° C. over half an hour, thencooled back to −78° C. and isobenzofuran-1,3-dione (3.4 g, 22.7 mmol) in25 ml of THF rapidly added. The reaction was allowed to warm up to RTand stirred overnight. Reaction mixture was concentrated down to 30 mL,diluted with 60 mL of water, cooled to 0° C. and acidified with 6N HClto pH4, and extracted with DCM (3×100 mL). The organic layers werecombined, dried over sodium sulfate and concentrated to dryness underreduced pressure. The resulting residue was triturated with DCM toafford 2-(4-methylthiazole-2-carbonyl)benzoic acid. MS m/z=248 [M+H]⁺.Calc'd for C₁₂H₉NO₃S: 247.3.

Step 2: Preparation of 4-(4-methylthiazol-2-yl)phthalazin-1(2H)-one

A RBF set up with stirring bar and reflux condenser was charged with2-(4-methylthiazole-2-carbonyl)benzoic acid (1.9 g, 7.7 mmol), hydrazine(1.3 mL, 226.9 mmol), and ethanol (40 mL, 0.2 M) while kept undernitrogen atmosphere. The reaction mixture was stirred under refluxovernight, then cooled to RT. The resulting precipitate was filtered offand washed with DCM to afford4-(4-methylthiazol-2-yl)phthalazin-1(2H)-one. MS m/z=244 [M+H]⁺. Calc'dfor C₁₂H₉N₃OS: 243.2.

Step 3: Preparation of 1-chloro-4-(4-methylthiazol-2-yl)phthalazine

A dry 50 mL RBF set up with stirring bar and reflux condenser wascharged with 4-(4-methylthiazol-2-yl)phthalazin-1(2H)-one (1.6 g, 6.6mmol) and phosphorus oxychloride (7.4 ml, 78.9 mmol). The mixture wasstirred under reflux for 18 hrs, then poured onto ice while stirringvigorously. To the iced mixture was added 6N NaOH until pH=9. Stirringwas continued vigorously until solids formed. The solids were filtered,washed with water and dried in oven to afford1-chloro-4-(4-methylthiazol-2-yl)phthalazine. MS m/z=262 [M+H]⁺. Calc'dfor C₁₂H₈ClN₃S: 261.7.

Example 467

Synthesis of4-(2-(4-(4-(4-methylthiazol-2-yl)phthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylphosphoramidic acid dihydroiodide

Step 1. To a yellow slurry ofN-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiazol-2-yl)phthalazin-1-amine(0.335 g, 0.664 mmol) and tetrabenzyl pyrophosphate (0.501 g, 0.930mmol) in 6.6 mL THF under nitrogen at 0° C. was added sodiumbis(trimethylsilyl)amide 1 M in THF (2.32 ml, 2.32 mmol) dropwise over 3min to give a deep red solution. The reaction was quenched with sat'daq. NaHCO₃, and diluted with EtOAc. The organic layer was washed 3× withsaturated aq. NaHCO₃, 1× brine, dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo. The material was purified by silicagel chromatography, ISCO, 40 g, 50 min run, 0-60% 90/10 DCM/MeOH in DCMto give dibenzyl4-(2-(4-(4-(4-methylthiazol-2-yl)phthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylphosphoramidatea yellow solid MS m/z=765 [M+H]⁺. Calc'd for C₄₁H₃₃N₈O₄PS: 764.8.

Step 2. To a slightly cloudy mixture of dibenzyl4-(2-(4-(4-(4-methylthiazol-2-yl)phthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylphosphoramidate(0.086 g, 0.11 mmol) in 3 mL 5:1 ACN/DCM was added iodotrimethylsilane(0.16 ml, 1.1 mmol) dropwise via syringe at ambient temperature undernitrogen. After 5 min, 0.6 mL MeOH was added and the stir bar wasremoved. The reaction was concentrated in vacuo and suspended in DCM andfiltered. The resulting orange solid was collected and dried in vacuo toprovide

4-(2-(4-(4-(4-methylthiazol-2-yl)phthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylphosphoramidicacid dihydroiodide as an orange solid. MS m/z=585 [M+H]⁺. Calculated forC₂₇H₂₁N₈O₄PS: 584.6.

Example 468

Step 1. 2-(2-Bromophenoxy)-5-nitropyrimidine

KH (6.29 g, 47.0 mmol, 30% in mineral oil) was washed with hexane underan argon atmosphere. Hexane was replaced with THF (62.7 ml, 18.8 mmol).The solution was cooled to 0° C. 2-Bromophenol (2.00 mL, 18.8 mmol) wasadded portion wise slowly at 0° C. The reaction was warmed to RT and awhite suspension formed. After 15 min, the bubbling ceased and2-chloro-5-nitropyrimidine (3.00 g, 18.8 mmol) was added portion wise atRT and a brown mixture formed. After 15 min, TLC showed the reaction tobe complete and a new polar product formed. Water and/or alcoholicsolvents were used in minimal quantities during reaction work up. Thecrude reaction material was passed through a pad of celite, washing withTHF under a cover of nitrogen. Caution is recommended to not allow thecelite pad to dry as KH is flammable and may ignite causing a fire. Thewet celite cake was immediately transferred into a RBF containing THF.The excess KH was quenched with water slowly under argon atmosphere. Thefiltrate was concentrated to afford a yellow solid. ¹H NMR showed mainlyproduct, 2-(2-bromophenoxy)-5-nitropyrimidine. MS Calcd for C₁₀H₆BrN₃O₃:[M]⁺=295. Found: [M+H]⁺=296, [M+2H]⁺=297.

Step 2. 2-(2-Bromophenoxy)pyrimidin-5-amine

To a solution of 2-(2-bromophenoxy)-5-nitropyrimidine (5.30 g, 17.9mmol) in DMF (35.8 ml, 17.9 mmol) was added tin (II) chloride (17.0 g,89.5 mmol) and water (4.48 ml, 17.9 mmol). The reaction was sonicatedfor 15 min and became deep red and exothermic in nature. The reactionwas stirred at RT. After 4 h, the reaction was diluted with EtOAc,cooled to 0° C. and neutralized with 10% NaOH. Tin residue precipitatedout of the solution. The reaction was diluted with EtOAc. The suspensionwas allowed to settle. The organic layer was decanted and passed througha fritted funnel. This procedure was repeated two more times to extractproduct into the organic layer. The organic layer, containing theproduct, was washed with brine, dried over MgSO₄, filtered, andconcentrated. The product was purified by column chromatography onsilica gel using 90:10 DCM:(90:10:1 DCM:MeOH:NH₄OH). Upon concentrationof the product fractions, the resulting brown solid wasdissolved/suspended in DCM, washed with water to remove the DMF, washedwith brine, dried over MgSO₄, filtered, and concentrated. Yellow solid,2-(2-bromophenoxy)pyrimidin-5-amine was obtained. MS Calc'd forC₁₀H₈BrN₃O: [M]⁺=265. Found: [M+H]⁺=266, [M+2H]⁺=267.

Step 3. N-(2-(2-Bromophenoxy)pyrimidin-5-yl)-4-phenylphthalazin-1-amine

2-(2-Bromophenoxy)pyrimidin-5-amine (3.01 g, 11.3 mmol),1-chloro-4-phenylphthalazine (2.72 g, 11.3 mmol), and butan-2-ol (56.6ml, 11.3 mmol) were placed in a sealed tube. The reaction vessel wassealed and mixture heated to 120° C. After 1.5 h, LCMS showed mainlyproduct as [M+H]⁺=470 and a small amount of bromo starting material. 200mg of phthalazine was added. After another 3.5 h, the reaction wascooled to RT. Hexane was added to allow a yellow solids to precipitate.The yellow solids were filtered and recrystallized with DCM and hexanes.The resulting dark brown solids were dried under vacuum overnight,affording the product,N-(2-(2-bromophenoxy)pyrimidin-5-yl)-4-phenylphthalazin-1-amine.

The filtrate was concentrated and the resulting residue purified bycolumn chromatography on silica gel using 90:10 DCM:(90:10:1DCM:MeOH:NH₄OH). Product fractions were concentrated to afford a secondcrop of the title compound as a brown solid. MS Calc'd for C₂₄H₁₆BrN₅O:[M]⁺=469. Found: [M+H]⁺=470, [M+2H]⁺=471.

Step 4.4-Phenyl-N-(2-(2-(pyridin-4-yl)phenoxy)pyrimidin-5-yl)phthalazin-1-amine

In an argon-purged sealed tube,N-(2-(2-bromophenoxy)pyrimidin-5-yl)-4-phenylphthalazin-1-amine (150 mg,319 μmol), pyridin-4-ylboronic acid (157 mg, 1.27 μmol), Pd(DPPF)Cl₂ (47mg, 64 μmol), sodium carbonate (239 μl, 478 μmol), and 1,4-dioxane (1.60ml, 319 μmol) were added. The reaction was stirred at RT for 5 min. Thetube was sealed and heated to 100° C. for 18 h. After 16 h, the reactionwas cooled to RT, diluted with EtOAc and 10 mL of water. The product wasextracted into EtOAc. The organic layer was washed with brine, driedover MgSO₄, filtered, and concentrated. The product was purified bycolumn chromatography on silica gel using 60:40 DCM:(90:10:1DCM:MeOH:NH₄OH). The resulting light brown solid was dissolved in 15 mLof DCM, the solvent were removed under vacuum, affording the titlecompound as a light brown solid. MS Calcd for C₂₉H₂₀N₆O: [M]⁺=468.Found: [M+H]⁺=469.

Example 469 Synthesis ofN-(4-(3-(2-Amino-5-fluoropyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amineStep 1.N-(4-(3-(2-Chloro-5-fluoropyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine

Under an argon atmosphere, 2,4-dichloro-5-fluoropyrimidine (390 mg, 2.34mmol) and 2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-ylboronicacid (1.01 g, 2.34 mmol) were dissolved in 1,2-dimethoxyethane (15.6 ml,2.34 mmol) in a screw capped test tube. Sodium carbonate (4.67 ml, 9.34mmol) was added followed by Pd(PPh₃)₄ (0.270 g, 0.234 mmol). The tubewas purged with argon, sealed, and heated to 85° C. After 3 h, LCMSshowed mostly product, a small amount of starting material left. 100 mgof Dichlorofluoropyrimidine was added, and the reaction was stirredovernight. After 22 h, LCMS showed complete conversion to product. Waterwas added. The product was extracted with DCM. The organic phase wasdried over MgSO₄, filtered, and concentrated. Hexane was added to theresidue. A tan solid precipitated and was filtered off with an aid ofhexane. The product was purified using an ISCO column chromatography onsilica gel eluting with 80:20 DCM:(90:10:1 DCM:MeOH:NH₄OH) and wasobtained as a yellow solid,N-(4-(3-(2-chloro-5-fluoropyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine(1.13 g, 93% yield). MS Calcd for C₂₉H₁₈ClFN₆O: [M]⁺=520. Found:[M+1]⁺=521.

Step 2. tert-Butyl5-fluoro-4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylcarbamate

The title compound was prepared according to the procedure described inGarnier, E.; Andoux, J.; Pasquinet, E.; Suzenet, F.; Poullain, D.;Lebret, B.; Guillaumet, G. J. Org. Chem. 2004, 69, 7809. Xantphos (281mg, 486 μmol) and 1,4-dioxane (12151 μl, 2430 μmol) were added into asealed tube. The tube was purged with argon, then palladium(II) acetate(55.0 mg, 243 μmol) was added. The mixture was stirred under argon for10 min. In a separate sealed tube,N-(4-(3-(2-chloro-5-fluoropyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine(1.27 mg, 2.43 mmol), tert-butyl carbamate (712 mg, 6.08 mmol),potassium carbonate (10.1 g, 72.9 mmol), and 1,4-dioxane (12.2 ml, 2.43mmol) were added. Then Pd(OAc)₂/Xantphos solution was added via asyringe. The resulting mixture was heated to 110° C. under argon withvigorous stirring. After 3.5 h, LCMS showed mainly product at 1.793 minas [M+H]⁺=602 and deBoc product at 1.602 min as [M+H]⁺=502. The reactionwas cooled to RT, diluted with DCM, passed through a pad of celite andsilica gel (1 cm thick each) with an aid of DCM and a bit of MeOH. Thefiltrate was concentrated to afford tert-Butyl5-fluoro-4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylcarbamate,which was carried on without further purification. MS Calcd forC₃₄H₂₈FN₇O₃: [M]⁺=601. Found: [M+1]⁺=602.

Step 3.N-(4-(3-(2-Amino-5-fluoropyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine

In a RBF, tert-butyl5-fluoro-4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylcarbamate(1.46 g, 2.43 mmol) was dissolved in DCM (4.86 ml, 2.43 mmol). TFA (749μl, 9.72 mmol) was added at RT. The reaction was stirred at RT. After 20min, LCMS showed mainly starting material. 1 mL of TFA was added and thereaction was allowed to stir at RT overnight. After 16 h, the reactionwas concentrated and the residue dissolved in DCM. The solution wascooled to 0° C. and neutralized with 2N NaOH. At pH=5-7, the product asa white solid precipitated out. At pH>7, the product dissolves in DCM.The precipitate was filtered with aid of DCM. The solid product was setaside, while the filtrate was concentrated. The residue was diluted witha bit of DCM. Water was added. Ether was added and the whole solutionwas triturated to precipitate out additional product. The solid wasfiltered off with an aid of Et₂O. This crop was combined with the firstcrop of solid. The product was purified by column chromatography on 120g silica gel using 70:30 DCM:(90:10:1 DCM:MeOH:NH₄OH). Fractionscontaining the product were combined, and concentrated, to afford an offwhite solid, which was triturated in Et₂O. The resulting yellow solidwas filtered off with an aid of Et₂O and air dried. The solids werepurified further via RPLC on the acidic Gilson Only fractions containingthe product were combined, diluted with DCM, and washed with sat.NaHCO₃. The organic was dried over MgSO₄, filtered, and concentrated toaffordN-(4-(3-(2-amino-5-fluoropyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine.MS Calcd for C₂₉H₂₀FN₇O: [M]⁺=501. Found: [M+1]⁺=502.

Example 470

Synthesis of methyl3-((4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)amino)-6-phenyl-4-pyridazinecarboxylate

A RBF was charged with 4-(dimethylamino)pyridine (5.4 mg, 44 μmol),3-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenylamino)-6-phenylpyridazine-4-carboxylicacid (210 mg, 440 μmol), methanol (53 μl, 1319 μmol) and 1.3 mL DCM. Themixture was cooled to 0° C. and 1,3-dicyclohexylcarbodiimide (100 mg,484 μmol) dissolved in 1.3 mL DCM was added. The heterogeneous mixturewas allowed to warm to RT and stirred for 4 h. 1.3 mL of DMF was addedand the reaction was stirred at RT for 72 h. The mixture was filteredthrough a pad of Celite, washing with DCM. The filtrate was concentratedtwice from toluene to remove excess DMF. The crude material was purifiedby silica gel chromatography, 0-10% MeOH/dDCM. Further purification wasdone by reverse phase chromatography, Gilson, 5-75% acetonitrile/0.1%TFA over 14 min to provide methyl3-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenylamino)-6-phenylpyridazine-4-carboxylatecleanly as a bright yellow solid. MS m/z=492 [M+H]⁺. Calc'd forC₂₇H₂₁N₇O₃: 491.50.

Example 471 Synthesis of 3-chloro-4-methoxy-6-phenylpyridazine

3,4-Dichloro-6-phenylpyridazine was synthesized from -oxobenzenebutanoicacid and 1-(phenylmethyl)hydrazine in 2 steps according to a procedureby Sircar (Sircar, I. J. Het. Chem. 1983, 20, 1473-1476.)3,4-Dichloro-6-phenylpyridazine (100 mg, 0.44 mmol) was combined withsodium methoxide (1.1 mL of a 0.50M solution in methanol, 0.55 mmol,1.25 equiv.) and methanol (296 μl, 1.5M) in a resealable tube and heatedto 65° C. for 1 hour. The methanol was evaporated in vacuo, and waterwas added to the residue. The mixture was extracted with DCM, dried overK₂CO₃, filtered and concentrated in vacuo, to afford3,4-dimethoxy-6-phenylpyridazine and3-methoxy-4-chloro-6-phenylpyridazine, the title compound, as a solid.

Example 472 Synthesis of 7-chloro-4-phenylfuro[3,2-d]pyridazine Step 1.N-tert-butylfuran-2-carboxamide

To a slurry of furan-2-carboxylic acid (10.0 g, 89 mmol) in 100 mL DCMat 0° C. under nitrogen was added DMF (0.069 ml, 0.89 mmol) and oxalylchloride (9.9 ml, 112 mmol) slowly in small portions over 5 min. Thereaction was allowed to warm to ambient temperature. After 3 h, theclear solution was concentrated in vacuo and the resulting oil wasdissolved in 75 mL THF and cooled to 0° C. A solution of tert-butylamine(28 ml, 268 mmol) in 25 mL THF was added dropwise over 1 h. The bath wasallowed to expire and the slurry was stirred over the weekend. Thereaction was concentrated in vacuo and partitioned between 1N NaOH andDCM. The aqueous layer was extracted twice with DCM. The combinedorganic layers were concentrated in vacuo to giveN-tert-butylfuran-2-carboxamide as a white solid. MS m/z=168 [M+H]⁺.Calc'd for C₉H₁₃NO₂: 167.2.

Step 2. 3-benzoyl-N-tert-butylfuran-2-carboxamide

To a stirring solution of N-tert-butylfuran-2-carboxamide (1.8 ml, 12mmol) in 100 mL DME under argon at −78° C. was added tert-butyllithium,1.7 M solution in pentane (14 ml, 24 mmol) slowly dropwise over 5 min.The heterogeneous reaction mixture was allowed to stir 1 h, at whichpoint a solution of N-tert-butylfuran-2-carboxamide (1.8 ml, 12 mmol) in10 mL DME was added over 5 min, dropwise. After 15 min, the bath wasremoved and the reaction was allowed to warm to ambient temperature. Thereaction was quenched by addition of saturated aqueous ammoniumchloride, water, and EtOAc. The organic layer was dried over anhydroussodium sulfate, filtered, and concentrated in vacuo. The resultingmaterial was purified by silica gel chromatography, ISCO, 80 g, 0-40%EtOAc/hexanes over 33 min to give a semi-solid. This material wastriturated 3× hexanes to give 3-benzoyl-N-tert-butylfuran-2-carboxamideas white crystals. MS m/z=272 [M+H]⁺. Calc'd for C₁₆H₁₇NO₃: 271.3.

Step 3. 3-benzoylfuran-2-carboxylic acid

To slurry of 3-benzoyl-N-tert-butylfuran-2-carboxamide (0.863 g, 3.18mmol) in 4 mL dioxane and 3 mL water was added sulfuric acid (1.02 ml,19.1 mmol). The mixture was sealed and heated to 120° C. for a total of48 h. Additional 3.0 equiv H₂SO₄ was added, and the reaction was heatedfor 8 h. The reaction was cooled and partitioned between water and DCM.The aqueous layer was extracted with DCM (4×), and the combined organicswere dried over anhydrous sodium sulfate, filtered, and concentrated invacuo to give 3-benzoylfuran-2-carboxylic acid as a brown semi-solid.This material was carried on without further purification. MS m/z=217[M+H]⁺. Calc'd for C₁₂H₈O₄: 216.2.

Step 4. 4-Phenylfuro[3,2-d]pyridazin-7-ol

A brown solution of 3-benzoylfuran-2-carboxylic acid (0.770 g, 3.56mmol) and anhydrous hydrazine (0.568 ml, 17.8 mmol) was heated to 100°C. in a sealed tube for approx. 72 h. The reaction was cooled, anddiluted with sat'd aq. NH₄Cl and EtOAc. The organic layer was washedwith sat'd aq. NH₄Cl and brine, and dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to give4-phenylfuro[3,2-d]pyridazin-7-ol which was carried on without furtherpurification. MS m/z=213 [M+H]⁺. Calc'd for C₁₂H₈H₂O₂: 212.2.

Step 5. Chloro-4-phenylfuro[3,2-d]pyridazine

A slurry of 4-phenylfuro[3,2-d]pyridazin-7-ol (0.327 g, 1.5 mmol) andpyridine (0.38 ml, 4.6 mmol) in 5 mL POCl₃ was heated with awater-cooled reflux condenser with drying tube to 130° C. for 3 h. Thebrown solution was cooled and the reaction judged complete by LCMS. Thereaction was poured onto ice with stirring. The solution was neutralizedwith 6 N NaOH and ice to control temperature. The resulting mixture wasextracted into DCM (3×). The combined organic extracts were dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. The solidwas adsorbed onto 2 g silica gel from DCM/MeOH and dried. The materialwas purified by silica gel chromatography, eluting with 0-20% EtOAc/DCMto give 7-chloro-4-phenylfuro[3,2-d]pyridazine as an off-white solid. MSm/z=231 [M+H]⁺. Calc'd for C₁₂H₇ClN₂O: 230.7.

Example 473

Synthesis of N1-(4-phenylphthalazin-1-yl)benzene-1,4-diamine

Benzene-1,4-diamine (0.337 g, 3.12 mmol) and1-chloro-4-phenylphthalazine (0.500 g, 2.08 mmol) were treated with 7.5mL 2-BuOH in a sealed tube and heated to 110° C. The reaction quicklybecame a solid, yellow mass. After several hours, the reaction wascooled and diluted with water. The slurry was then partitioned betweenDCM and 1N NaOH. The aqueous layer was extracted into DCM (2×). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo. The resulting material was purifiedby silica gel chromatography, ISCO, 40 g, 0-10% MeOH/MC to giveN1-(4-phenylphthalazin-1-yl)benzene-1,4-diamine as an orange-brownsolid. MS m/z=313 [M+H]⁺. Calc'd for C₂₀H₁₆N₄: 312.4.

Example 474 Synthesis of 4-(3-Bromopyridin-2-yloxy)benzenamine

3-Bromo-2-chloropyridine (10.3 g, 53.4 mmol), 4-aminophenol (7.00 g,64.1 mmol), cesium carbonate (34.8 g, 107 mmol), and DMSO (53 ml, 53.4mmol) were added into a pressure tube. The tube was capped and placed ina preheated oil bath at 130° C. After 16 h, the reaction mixture wasstirred and cooled in ice-water. Water was added slowly to the mixtureand the product precipitated out as a gray solid. The solids were washedwith water, dried under vacuum at RT to afford4-(3-bromopyridin-2-yloxy)benzenamine. MS Calcd for C₁₁H₉BrN₂O:[M]⁺=264. Found [M+H]⁺=265.

Example 475

Synthesis of4-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)benzenamine

Into a sealed tube was added 4-(3-bromopyridin-2-yloxy)benzenamine (5.38g, 20.0 mmol), 1,4-dioxane (101 ml, 20.0 mmol), and potassium acetate(6.00 g, 61.0 mmol). The tube was purged with argon. Then PdCl₂(DPPF)(0.700 g, 1.00 mmol) and4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(13.0 g, 53.0 mmol) were added. The reaction mixture was stirred for 0.5h at rt until a deep brown solution was formed. The reaction tube wasthen placed in a preheated oil bath at 85° C. After 18 h, the reactionwas cooled to rt and passed through a pad of celite with an aid of EtOActo remove the black impurities. The filtrate was concentrated to give abrown oil. The oil was placed under vacuum over the weekend and became asolid of4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)benzenamine.MS Calcd for C₁₇H₂₁BN₂O₃: [M]⁺=312. Found: [M+H]⁺=313.

Example 476

Synthesis of 1H-Pyrrolo[2,3-b]pyridine

The title compound was prepared according to the procedure described inWO2003082289A1. A solution of 1H-pyrrolo[2,3-b]pyridine (10.0 g, 84.6mmol) in EtOAc (846 ml, 84.6 mmol) was cooled to 0° C. To the coldsolution was added a solution of mCPBA (103 mmol, 23.1 g, 77% pure) in53 mL of EtOAc over a period of 1.5 h. An additional 100 mL of EtOAc wasadded to dilute the reaction. The residual of mCPBA was washed into thereaction mixture by an additional portion of EtOAc (25 mL). A lot ofsolid precipitated out of the solution. The resulting solution waswarmed to rt, and allowed to stir at RT for 3 h. The reaction mixturewas cooled to 0° C. and the resulting slurry was filtered to collect theN-oxide as the meta-chlorobenzoic acid salt. The solid was washed withadditional EtOAc and dried under vacuum. The product,1H-pyrrolo[2,3-b]pyridine 1-oxide salt of mCBA was obtained as lightyellow solid. ¹H NMR in deuterated MeOH indicated predominately the mCBAsalt of the N-oxide.

The mCBA salt was treated with aqueous base to liberate the N-oxide. Aslurry of the N-oxide mCBA salt (35.5 g, 265 mmol) in 149 mL ofdeionized water at 15° C. was treated with sufficient amount of aqueoussolution containing 30% by weight of potassium carbonate (11.0 g, 79.4mmol) to raise the pH of the slurry between 9.5 to 10.5. Additionalwater (74 mL) was added to the mixture while the temperature wasmaintained between 15° C. to rt for 2 h. The slurry was cooled to 0° C.for 5 h, and then filtered to recover the precipitate. The precipitatewas washed with water and dried to afford the white N-oxide product,1H-pyrrolo[2,3-b]pyridine 1-oxide. ¹H NMR (Bruker, 400 MHz, CD₃OD): 8.23(d, J=6.3 Hz, 1H), 7.94 (d, J=8.1 Hz, 1H), 7.52 (d, J=3.3 Hz, 1H), 7.22(m, 1H), 6.71 (d, J=3.3 Hz, 1H).

Example 477

Synthesis of 4-Chloro-1H-pyrrolo[2,3-b]pyridine

The title compound was prepared according to the procedure described inWO2003082289A1. A solution of azaindole N-oxide (6.82 g, 51.0 mmol) inDMF (36.0 ml, 470 mmol) was heated to 50° C. Methanesulfonyl chloride(11.0 ml, 137 mmol) was added to the heated solution at such a rate asto maintain the reaction temperature at 65 to 75° C. The resultingmixture was heated at 68-77° C. until the reaction was judged completeby RPLC. The total reaction time was 4 hours. The reaction was cooled tort and quenched with water (10 mL). The mixture was cooled to 5° C. 10 NNaOH solution was added to raise the pH of the solution to 7. Theresulting slurry was warmed to rt, agitated for 1 h, and then filteredto collect the product. The product was washed with additional water anddried under vacuum. Rusty solid, 4-chloro-1H-pyrrolo[2,3-b]pyridine wascollected. ¹H NMR (Bruker, 400 MHz, DMSO-d6) 12.0 (br s, 1H), 8.19 (d,J=5.4 Hz, 1H), 7.60 (t, J=3.0 Hz, 1H), 7.20 (d, J=5.0 Hz, 1H), 6.52 (d,J=3.0 Hz, 1H).

Example 478

Synthesis of tert-Butyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (3.00 g, 19.7 mmol),N,N-dimethylpyridin-4-amine (1.20 g, 9.83 mmol), dichloromethane (67.8ml, 19.7 mmol) was added di-tert-butyl dicarbonate (4.72 g, 21.6 mmol).The resulting mixture was stirred at rt under nitrogen. After 18 h, thereaction mixture was diluted with CH₂Cl₂, washed with saturated sodiumbicarbonate, and washed with brine. The organic phase was dried overmagnesium sulfate, filtered, and concentrated. Performing ISCO columnchromatography on silica gel using 90:10 Hex:EtOAc afforded the productas a colorless oil. The oil was placed in the vacuum oven overnight toremove EtOAc. White solid, tert-butyl4-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate formed slowly undervacuum. MS Calcd for C₁₂Hl₃ClN₂O₂: [M]⁺=252. Found: [2M+Na]⁺=527.

Example 479

Synthesis of 3,3-Dibromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-2(3H)-one

The title compound was prepared according to the procedure described inWO2001046196A1. To a stirred suspension of4-chloro-1H-pyrrolo[2,3-b]pyridine (2.00 g, 13.1 mmol) in t-BuOH (131ml, 13.1 mmol) was added pyridinium tribromide (14.1 g, 44.2 mmol) bysmall portions. The solution was stirred at rt for 2 h. After 3 h, LCMSshowed product and mono brominated product. 5.00 g of pyridiniumtribromide was added. After 1.5 h, LCMS showed mainly product and excesspyridinium tribromide. After another 0.5 h, water was added and thewhole was diluted with EtOAc until all solids were dissolved. Theproduct was extracted with EtOAc. The organic layer was washed withbrine, dried over MgSO₄, filtered, and concentrated. Trituration of thecrude product with hexanes gave an orange solid. ¹H NMR confirmed theproduct, 3,3-dibromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (4.07g, 95% yield). The product was insoluble in DCM and CHCl₃. MS Calcd forC₇H₃Br₂ClN₂O: [M]¹=324. Found: [M+H]⁺=325, [M+3H]⁺=327.

Example 480

Synthesis of 4-Chloro-1H-pyrrolo[2,3-b]pyridin-2(3H)-one

The title compound was prepared according to the procedure described inWO2001046196A1. A mixture of3,3-dibromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-2 (3H)-one (4.07 g, 12.5mmol), zinc dust (8.15 g, 125 mmol), AcOH (54.2 ml, 12.5 mmol), and MeOH(54.2 ml, 12.5 mmol) was stirred at rt. After 3 h, the reaction mixturewas passed through a pad of celite with an aid of EtOAc. The filtratewas then diluted with brine. The whole was extracted with EtOAc. Theorganic layer was further washed with brine, dried over MgSO₄, filtered,concentrated. The product was purified by column chromatography onsilica gel using 70:30 DCM:(90:10:1 DCM:MeOH:NH₄OH). Fractionscontaining the product were concentrated. White cotton-like solid,4-chloro-1H-pyrrolo[2,3-b]pyridin-2(3H)-one was obtained. MS Calcd forC₇H₅ClN₂O: [M]⁺=168. Found: [M+H]⁺=169.

Example 481

Synthesis of 6-(3-Bromopyridin-2-yloxy)pyridin-3-amine

3-Bromo-2-chloropyridine (7.27 g, 37.8 mmol), 5-aminopyridin-2-ol (4.99g, 45.3 mmol), freshly ground cesium carbonate (36.9 g, 113 mmol), andDMSO (37.8 ml, 37.8 mmol) were added into a glass round bottom pressurevessel equipped with a stir bar. The vessel was sealed and placed in apreheated oil bath at 130° C. After 18 h, the reaction was diluted withEtOAc (4×250 mL) and the whole solution was sonicated. After the solidwas settled, the top solution was decanted through a pad of celite andsilica gel (each layer was 1 cm). This procedure was repeated for thesalt residue which left in the flask to remove the product and DMSO fromthe salt. The filtrate was concentrated to give an oil which includedthe product and DMSO. The product was extracted with EtOAc (3×300 mL)and DCM (1×100 mL). The EtOAc and DCM layers were washed separately witha minimum amount of brine. The organic phases were dried separately overa minimum amount of MgSO₄. The MgSO₄ was filtered off and the filtrateswere combined and concentrated. A wet, light green solid was obtained.The solid was triturated with hexanes. The solid was filtered off,collected, and dried under vacuum. The product,6-(3-bromopyridin-2-yloxy)pyridin-3-amine was collected as tan solids. Asecond batch was obtained from the filtrate. The filtrate wasconcentrated to give an oil. The oil was purified by ISCO columnchromatography using 90:10 DCM:(90:10:1 DCM:MeOH:NH₄OH). A light yellowsolid, was obtained, dried under vacuum, and given a sample ID: A wet,green solid was obtained, dried under vacuum. MS Calcd for C₁₀H₈BrN₃O:[M]⁺=265. Found [M+1]⁺=266.

Example 482

Synthesis of tert-Butyl 4-chloropicolinoyl(methyl)carbamate

The title compound was prepared according to the procedure described inreferences: Marino, J. P.; Rubio, M. B.; Cao, G.; de Dios, A. J. Am.Chem. Soc. 2002, 124, 13398. (b) Diaz, D. D.; Finn, M. G. Org. Lett.2004, 6, 43. (c) Padwa, A.; Brodney, M. A.; Lynch, S. M.; Rashatasakhon,P.; Wang, Q.; Zhang, H. J. Org. Chem. 2004, 69, 3735).

A solution of 4-chloro-N-methylpicolinamide (1.00 g, 5.86 mmol) in THF(11.7 ml, 5.86 mmol) was cooled to −78° C. Then n-BuLi (2345 μl, 5862μmol) in THF was added dropwise at −78° C. A thick yellow suspension wasformed in 5 min. The suspension was stirred at −78° C. for 30 min, thenwarmed to 0° C., stirred at this temperature for 10 min, and cooled backdown to −78° C. Di-tert-butyl dicarbonate (2.30 mg, 10.6 mmol) in 5 mLof THF was added dropwise. The reaction was stirred at −78° C. for 0.5 hand at 0° C. for 20 min, and warmed to rt for 10 min. LCMS showedproduct at 2.231 min composed of [M]⁺, [M+Na]⁺, [2M+Na]⁺; and startingmaterial at 1.631 min in a ratio of 1:3. After 20 min, LCMS showed moreproduct formed. The reaction was stirred at rt for 2 days. After 2 days,LCMS showed 1:1 Prod:SM. The reaction was stopped. The whole wasextracted with EtOAc, washed with brine, dried over MgSO₄, filtered, andconcentrated. The product was purified by performing columnchromatography on silica gel using 80:20 Hex:EtOAc. ¹H NMR showed mainlyproduct. The product, tert-butyl 4-chloropicolinoyl(methyl)carbamate(849 mg, 54% yield) was collected as light yellow solid. MS Calculatedfor C₁₂H₁₅ClN₂O₃: [M]⁺=270. Found [2M+Na]⁺=563.

Example 483

Synthesis of 3-(3-Chloropropyl)-2-fluoro-4-iodopyridine

To a −78° C. solution of 2-fluoro-3-iodopyridine (186 mg, 834 μmol) intetrahydrofuran (4171 μl, 834 μmol) was added a solution of 2M LDA (500μl, 1.00 mol) in heptane/THF at −78° C. After 1 h at −78° C.,1-chloro-3-iodopropane (512 mg, 2.50 mmol) in 0.5 mL of THF was added tothe anion solution slowly at −78° C. After 30 min at −78° C., thereaction was warmed to rt and stirred overnight. The reaction wasdiluted with DCM, washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by performing a columnchromatography on silica gel using 95:05 Hex:EtOAc. Fractions containingthe product were concentrated. ¹H NMR showed product,3-(3-chloropropyl)-2-fluoro-4-iodopyridine. Light yellow liquid/solidmixture was collected. MS Calcd for C₈H₈ClFIN: [M]⁺=299. Found:[M+H]⁺=300. HRMS Calcd for C₈H₈ClFIN: [M]⁺=298.9447. Found:[M+H]⁺=299.9752. mp=24-25° C.

Example 484

Synthesis of 5-Iodo-1,2,3,4-tetrahydro-1,8-naphthyridine

3-(3-Chloropropyl)-2-fluoro-4-iodopyridine (3.31 g, 11 mmol), ammoniumhydroxide (71 mL, 20 ml, 553 mmol, 28.0-30.0%), ammonium acetate (12 g,155 mmol), potassium iodide (3.9 g, 23 mmol), potassium carbonate (7.6g, 55 mmol), and DMF (22 ml, 11 mmol) were added into a sealed tube. Thetube was sealed and placed in an oil bath at 60° C. After 7 h, thereaction was cooled down to rt. Colorless crystals was formed. Thereaction was diluted with EtOAc. The organic layer was extracted withEtOAc, washed with brine, dried over MgSO₄, filtered, and concentrated.The product was purified by column chromatography on silica gel usingHex and 70:30 Hex:EtOAc. A suspension was obtained. This suspension wasdiluted with DCM, washed with water to remove the DMF, washed withbrine, dried over MgSO₄, filtered, and concentrated. Off white solid wasobtained. ¹H NMR was showed mainly product,5-iodo-1,2,3,4-tetrahydro-1,8-naphthyridine. This material was carriedto the next step. ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, J=5.3 Hz, 1H), 7.01(d, J=5.3 Hz, 1H), 4.90 (br s, 1H), 3.39. mp=117-118° C.

Example 485

Synthesis of tert-Butyl 2-(2-fluoro-4-iodopyridin-3-yl)ethylcarbamate

To −78° C. solution of 2-fluoro-3-iodopyridine (7.61 g, 34.1 mmol) intetrahydrofuran (171 ml, 34.1 mmol) was added a solution of 2M LDA (20.5ml, 41.0 mmol) in heptane/THF at −78° C. After 1 h 20 min at −78° C.,sulfamidate (9.90 g, 44.4 mmol) in 80 mL of THF was added to the anionsolution slowly at −78° C. over 10 min. After 30 min, the reaction waswarmed to rt and the reaction was stirred overnight. The solvent wasevaporated and the residue was diluted with 70 mL of water and treatedwith 6 N HCl until the pH=1. After 1.5 h, an aliquot was removed,diluted with EtOAc, and neutralized with sat NaHCO₃. LCMS of the organiclayer showed tert-butyl 2-(2-fluoro-4-iodopyridin-3-yl)ethylcarbamate at2.250 min as [M+H]⁺=367. After 2 h, the reaction was cooled to 0° C.,100 mL of DCM was added, and the whole was neutralized slowly with sat.NaHCO₃ and solid NaHCO₃ to pH=7. The product was extracted with DCM(3×100 mL). The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated. The residue was purified by columnchromatography on silica gel using 80:20 Hex:EtOAc to collect theproduct. Viscous yellow oil became a light tan solid. ¹H NMR showedmainly product, tert-butyl2-(2-fluoro-4-iodopyridin-3-yl)ethylcarbamate. MS Calcd forC₁₂H₁₆FIN₂O₂: [M]⁺=366. Found: [M+H]⁺=367. HRMS Calcd for C₁₂H₁₆FIN₂O₂:[M]⁺=366.0313. Found: [M+H]⁺=367.0324.

Example 486

Synthesis of 2-(2-Fluoro-4-iodopyridin-3-yl)ethanamine

TFA (0.677 ml, 8.79 mmol) was added into a solution of tert-butyl2-(2-fluoro-4-iodopyridin-3-yl)ethylcarbamate (1.61 g, 4.40 mmol) in DCM(6.28 ml, 4.40 mmol). After 4 h, LCMS showed mainly starting material. 1mL of TFA was added. After 16 h, the reaction was diluted with DCM,neutralized with sat. NaHCO₃. The product was extracted with DCM. Theorganic layer was washed with brine, dried over MgSO₄, and concentratedto afford a creamy colored solid,2-(2-fluoro-4-iodopyridin-3-yl)ethanamine MS Calcd for C₇H₈FIN₂:[M]⁺=266. Found: [M+H]⁺=267. HRMS Calcd for C₇H₈FIN₂: [M+H]⁺=266.9789.Found: [M+H]⁺=266.9802.

Example 487

Synthesis of 4-Iodo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

2-(2-Fluoro-4-iodopyridin-3-yl)ethanamine (666 mg, 2503 μmol), potassiumcarbonate (727 mg, 5.26 mmol), and DMF (5.00 ml, 2.50 mmol) were addedinto a sealed tube. The tube was sealed and placed in an oil bath at 60°C. After 23 h, the reaction was diluted with DCM, washed with brine,dried over MgSO₄, filtered, and concentrated. The residue was dissolvedin 50 mL of DCM and washed with water (3×30 mL) to remove DMF. Theorganic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. Dark orange solid (semi-liquid) was obtained. ¹H NMRshowed mainly desired cyclized product,4-iodo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine. MS Calcd for C₇H₇IN₂:[M]⁺=246. Found: [M+H]⁺=247.

Example 488

Synthesis of2-(4-(4-Phenylphthalazin-1-ylamino)phenoxy)pyridin-3-ylboronic acid

2-(4-Aminophenoxy)pyridin-3-ylboronic acid (478 mg, 2.08 mmol),1-chloro-4-phenylphthalazine (500 mg, 2.08 mmol) and butan-2-ol (4.16ml, 2.08 mmol) were placed in a sealed tube. The reaction vessel wassealed and the mixture heated to 100° C. After 1 h 45 min, the reactionwas cooled to rt. Hexane was added and the precipitated tan solid wasfiltered off with hexanes. LCMS of the solids indicated product,2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-ylboronic acid. MSCalculated for C₂₅H₁₉BN₄O: [M]⁺=434. Found: [M+1]⁺=435.

Example 489

Synthesis of 3-chloro-4-ethyl-6-phenylpyridazine

A RBF was charged with 3-chloro-4-methyl-6-phenylpyridazine (5.0 g, 24mmol) and 120 mL of THF under nitrogen, and the solution was cooled to−78° C. Lithium diisopropylamide, 2.0M in heptane/THF/ethylbenzene (15ml, 29 mmol) was added and the mixture was stirred at −78° C. for 5 min,followed by RT for 1 h. The mixture was cooled to −78° C. and methyliodide (1.8 ml, 29 mmol), which had been passed through a plug of basicalumina prior to use, was added dropwise. After stirring at −78° C. for5 min, the reaction was stirred at RT for 0.5 h. Water was added toquench the reaction, and the mixture was concentrated and partitionedbetween dichloromethane and water. The layers were separated and theaqueous portion was extracted with additional DCM. The combined organicswere dried with MgSO₄, filtered and concentrated. The crude material waspurified by silica gel chromatography (100% DCM to 95/5 DCM/MeOH) toprovide 3-chloro-4-ethyl-6-phenylpyridazine as a tan solid. MS m/z=219[M+H]⁺. Calc'd for C₁₂H₁₁ClN₂: 218.68.

Example 490

Synthesis of 4-ethyl-N-(4-methoxyphenyl)-6-phenylpyridazin-3-amine

A pressure bottle was charged with 3-chloro-4-ethyl-6-phenylpyridazine(1.00 g, 4.57 mmol), 1,4-anisidine (0.526 ml, 4.57 mmol),tris(dibenzylideneacetone)dipalladium (0) (0.105 g, 0.114 mmol), S-Phos(0.188 g, 0.457 mmol), sodium tert-butoxide (0.615 g, 6.40 mmol) and13.8 mL of toluene. The bottle was sealed and the reaction mixture washeated 100° C. for 1 h. Upon cooling, the mixture was diluted with DCMand washed with water. The organic portion was dried with MgSO₄,filtered and concentrated. The crude material was purified by silica gelchromatography using 5% MeOH/DCM to provide4-ethyl-N-(4-methoxyphenyl)-6-phenylpyridazin-3-amine as a tan solid. MSm/z=306 [M+H]⁺. Calc'd for C₁₉H₁₉N₃O: 305.37.

Example 491

Synthesis of 4-(4-ethyl-6-phenylpyridazin-3-ylamino)phenol

A RBF was charged with 13.9 mL of 1:1 AcOH:HBr and4-ethyl-N-(4-methoxyphenyl)-6-phenylpyridazin-3-amine (1.27 g, 4.16mmol). The flask was fitted with a reflux condenser and was heated at140° C. for 4 h. Upon cooling, the reaction mixture was poured into icewater and brought to neutral pH by careful addition of 2M aqueousNa₂CO₃. The resulting precipitate was filtered, washed with water anddried under vacuum to provide4-(4-ethyl-6-phenylpyridazin-3-ylamino)phenol as a tan solid. MS m/z=292[M+H]⁺. Calc'd for C₁₈H₁₇N₃O: 291.35.

Example 492

Synthesis of 3-Chloro-6-phenylpyridazine-4-carboxylic acid

A 250 mL RBF was charged with 56 mL of anhydrous THF, cooled to −78° C.and kept under nitrogen atmosphere. Butyllithium (2.5 M, 5770 μl, 14426μmol) was added, followed by 2,2,6,6-tetramethylpiperidine (2656 μl,15737 μmol). The mixture was warmed to 0° C., stirred at thattemperature for 0.5 h, then re-cooled to −78° C.3-chloro-6-phenylpyridazine (2.5 g, 13114 μmol) was dissolved in aseparate pot in warm THF (˜20 mL) and was added via syringe quickly andin portions to avoid precipitation. The mixture became dark red uponaddition, and was stirred for 0.5 h at −78° C. Carbon dioxide (s) wasadded to a separate pot fitted with a drying tube and was connected tothe reaction mixture via additional tubing. After exposure to carbondioxide (g), the reaction mixture was stirred at −78° C. for 10 min. Thereaction was quenched by addition of 25 mL 25% conc. HCl/THF and wasallowed to warm to RT. The mixture was diluted with DCM and washed withwater. The organic portion was washed with 1 M NaHCO₃ twice. The aqueousportion was carefully acidified with conc. HCl upon which the productcrashed out. The solid was filtered, washed with water and dried toprovide 3-chloro-6-phenylpyridazine-4-carboxylic acid. MS m/z=235[M+H]⁺. Calc'd for C₁₁H₇ClN₂O₂: 234.64.

The invention further provides methods for making compounds of FormulasI-III. For example, and in one embodiment, there is provided a method ofmaking a compound of Formula 1, the method comprising the step ofreacting compound of Formula A

with a compound of Formula B

wherein C¹, C², D, L¹, Z and R³⁻⁴ of compound of formula A and A¹, A²and R⁶⁻⁸ of compound of formula B are as defined herein, and X is ahalogen, to make a compound of Formula I. This method may also be usedto make a compound of Formulas II and III.

While the examples described above provide processes for synthesizingcompounds of Formulas I-III, other methods may be utilized to preparesuch compounds. In the procedures described herein, the steps may beperformed in an alternate order and may be preceded, or followed, byadditional protection/deprotection steps as necessary.

Methods involving the use of protecting groups may be used.Particularly, if one or more functional groups, for example carboxy,hydroxy, amino, or mercapto groups, are or need to be protected inpreparing the compounds of the invention, because they are not intendedto take part in a specific reaction or chemical transformation, variousknown conventional protecting groups may be used. For example,protecting groups typically utilized in the synthesis of natural andsynthetic compounds, including peptides, nucleic acids, derivativesthereof and sugars, having multiple reactive centers, chiral centers andother sites potentially susceptible to the reaction reagents and/orconditions, may be used.

The protecting groups may already be present in precursors and shouldprotect the functional groups concerned against unwanted secondaryreactions, such as acylations, etherifications, esterifications,oxidations, solvolysis, and similar reactions. It is a characteristic ofprotecting groups that they readily lend themselves, i.e. withoutundesired secondary reactions, to removal, typically accomplished bysolvolysis, reduction, photolysis or other methods of removal such as byenzyme activity, under conditions analogous to physiological conditions.It should also be appreciated that the protecting groups should not bepresent in the end-products. Those of ordinary skill in the art know, orcan easily establish, which protecting groups are suitable with thereactions described herein.

The protection of functional groups by protecting groups, the protectinggroups themselves, and their removal reactions (commonly referred to as“deprotection”) are described, for example, in standard reference works,such as J. F. W. McOmie, Protective Groups in Organic Chemistry, PlenumPress, London and New York (1973), in T. W. Greene, Protective Groups inOrganic Synthesis, Wiley, New York (1981), in The Peptides, Volume 3, E.Gross and J. Meienhofer editors, Academic Press, London and New York(1981), in Methoden der Organischen Chemie (Methods of OrganicChemistry), Houben Weyl, 4^(th) edition, Volume 15/1, Georg ThiemeVerlag, Stuttgart (1974), in H.-D. Jakubke and H. Jescheit, Aminosäuren,Peptide, Proteine (Amino Acids, Peptides, Proteins), Verlag Chemie,Weinheim, Deerfield Beach, and Basel (1982), and in Jochen Lehmann,Chemie der Kohlenhydrate: Monosaccharide and Derivate (Chemistry ofCarbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag,Stuttgart (1974).

The procedures may further use appropriate reaction conditions,including inert solvents, additional reagents, such as bases (e.g., LDA,DIEA, pyridine, K₂CO₃, and the like), catalysts, and salt forms of theabove. The intermediates may be isolated or carried on in situ, with orwithout purification. Purification methods are known in the art andinclude, for example, crystallization, chromatography (liquid and gasphase, and the like), extraction, distillation, trituration, reversephase HPLC and the like, many of which were utilized in the Examplesabove. Reactions conditions such as temperature, duration, pressure, andatmosphere (inert gas, ambient) are known in the art and may be adjustedas appropriate for the reaction.

All synthetic procedures described herein can be carried out either inthe absence or in the presence (usually) of solvents or diluents. Asappreciated by those of ordinary skill in the art, the solvents shouldbe inert with respect to, and should be able to dissolve, the startingmaterials and other reagents used. Solvents should be able to partiallyor wholly solubilize the reactants in the absence or presence ofcatalysts, condensing agents or neutralizing agents, for example ionexchangers, typically cation exchangers for example in the H⁺ form. Theability of the solvent to allow and/or influence the progress or rate ofthe reaction is generally dependant on the type and properties of thesolvent(s), the reaction conditions including temperature, pressure,atmospheric conditions such as in an inert atmosphere under argon ornitrogen, and concentration, and of the reactants themselves.

Suitable solvents for conducting reactions to synthesize compounds ofthe invention include, without limitation, water; esters, includinglower alkyl-lower alkanoates, e.g., EtOAc; ethers including aliphaticethers, e.g., Et₂O and ethylene glycol dimethylether or cyclic ethers,e.g., THF; liquid aromatic hydrocarbons, including benzene, toluene andxylene; alcohols, including MeOH, EtOH, 1-propanol, IPOH, n- andt-butanol; nitriles including CH₃CN; halogenated hydrocarbons, includingCH₂Cl₂, CHCl₃ and CCL₄; acid amides including DMF; sulfoxides, includingDMSO; bases, including heterocyclic nitrogen bases, e.g. pyridine;carboxylic acids, including lower alkanecarboxylic acids, e.g., AcOH;inorganic acids including HCl, HBr, HF, H₂SO₄ and the like; carboxylicacid anhydrides, including lower alkane acid anhydrides, e.g., aceticanhydride; cyclic, linear, or branched hydrocarbons, includingcyclohexane, hexane, pentane, isopentane and the like, and mixtures ofthese solvents, such as purely organic solvent combinations, orwater-containing solvent combinations e.g., aqueous solutions. Thesesolvents and solvent mixtures may also be used in “working-up” thereaction as well as in processing the reaction and/or isolating thereaction product(s), such as in chromatography.

The invention further includes salt forms of compounds of Formulas I, IIand III. Salts of a compound of the invention having a salt-forminggroup may be prepared in a conventional manner or manner known topersons skilled in the art. For example, acid addition salts ofcompounds of the invention may be obtained by treatment with an acid orwith a suitable anion exchange reagent. A salt with two acid molecules(for example a dihalogenide) may also be converted into a salt with oneacid molecule per compound (for example a monohalogenide); this may bedone by heating to a melt, or for example by heating as a solid under ahigh vacuum at elevated temperature, for example from 50° C. to 170° C.,one molecule of the acid being expelled per molecule of the compound.

Acid salts can usually be converted to free-base compounds, e.g. bytreating the salt with suitable basic agents, for example with alkalimetal carbonates, alkali metal hydrogen carbonates, or alkali metalhydroxides, typically potassium carbonate or sodium hydroxide. Suitableacid and base addition salts are further described in the DefinitionSection herein.

The invention further encompasses pro-drugs of compounds of Formulas I,II and III. For example, a phosphate group may be a pro-drug derivativeof an alcohol group or an amine group, or an ester may be a pro-drug ofa carboxylic acid functional group. See Example 476 herein forpreparation of a phosphate group. Phosphate groups may be incorporatedinto desired compounds of Formulas I, II and III in order to improveupon in-vivo bioavailability and/or other pharmacokinetic orpharmacodynamic properties of the compound.

The invention further encompasses “intermediate” compounds, includingstructures produced from the synthetic procedures described, whetherisolated or not, prior to obtaining the finally desired compound.Structures resulting from carrying out steps from a transient startingmaterial, structures resulting from divergence from the describedmethod(s) at any stage, and structures forming starting materials underthe reaction conditions are all “intermediates” included in theinvention. Further, structures produced by using starting materials inthe form of a reactive derivative or salt, or produced by a compoundobtainable by means of the process according to the invention andstructures resulting from processing the compounds of the invention insitu are also within the scope of the invention.

Starting materials of the invention, are either known, commerciallyavailable, or can be synthesized in analogy to or according to methodsthat are known in the art. Many starting materials may be preparedaccording to known processes and, in particular, can be prepared usingprocesses described in the examples. In synthesizing starting materials,functional groups may be protected with suitable protecting groups whennecessary. Protecting groups, their introduction and removal aredescribed above.

Compounds of the present invention can possess, in general, one or moreasymmetric carbon atoms and are thus capable of existing in the form ofoptical isomers as well as in the form of racemic or non-racemicmixtures thereof. The optical isomers can be obtained by resolution ofthe racemic mixtures according to conventional processes, e.g., byformation of diastereoisomeric salts, by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of theinvention with chiral reagents, such as an optically pure acid in anactivated form or an optically pure isocyanate. The synthesizeddiastereoisomers can be separated by conventional means such aschromatography, distillation, crystallization or sublimation, and thenhydrolyzed to deliver the enantiomerically pure compound. The opticallyactive compounds of the invention can likewise be obtained by usingoptically active starting materials. These isomers may be in the form ofa free acid, a free base, an ester or a salt.

The compounds of this invention may also be represented in multipletautomeric forms. The invention expressly includes all tautomeric formsof the compounds described herein.

The compounds may also occur in cis- or trans- or E- or Z-double bondisomeric forms. All such isomeric forms of such compounds are expresslyincluded in the present invention. All crystal forms of the compoundsdescribed herein are expressly included in the present invention.

Substituents on ring moieties (e.g., phenyl, thienyl, etc.) may beattached to specific atoms, whereby they are intended to be fixed tothat atom, or they may be drawn unattached to a specific atom, wherebythey are intended to be attached at any available atom that is notalready substituted by an atom other than H (hydrogen).

The synthetic chemistry transformations, as well as protecting groupmethodologies (protection and deprotection) described above and usefulin synthesizing the inhibitor compounds described herein, are known inthe art and include, for example, those such as described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^(rd)edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); A.Katritzky and A. Pozharski, Handbook of Heterocyclic Chemistry, 2^(nd)edition (2001); M. Bodanszky, A. Bodanszky, The Practice of PeptideSynthesis, Springer-Verlag, Berlin Heidelberg (1984); J. Seyden-Penne,Reductions by the Alumino- and Borohydrides in Organic Synthesis, 2^(nd)edition, Wiley-VCH, (1997); and L. Paquette, editor, Encyclopedia ofReagents for Organic Synthesis, John Wiley and Sons (1995).

The compounds of the invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and include those which increasebiological penetration into a given biological compartment (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion. By way of example, a compound ofthe invention may be modified to incorporate a hydrophobic group or“greasy” moiety in an attempt to enhance the passage of the compoundthrough a hydrophobic membrane, such as a cell wall.

Biological Evaluation

Although the pharmacological properties of the compounds of theinvention (Formulas I-III) vary with structural change, in general,activity possessed by compounds of Formulas I-III may be demonstratedboth in vitro as well as in vivo. The following exemplifiedpharmacological assays have been carried out with the compoundsaccording to the invention. Briefly, representative compounds of theinvention were found to inhibit the activity of Aurora kinaseselectively or non-selectively, at doses less than 25 μM. This activitydemonstrates the utility of the compounds in the prophylaxis andtreatment of cellular proliferative disorders, including cancer asdescribed herein.

Aurora Kinase HTRF Assays AuroraA-TPX2-Homogeneous Time ResolvedFluorescent (HTRF) Kinase Assay

The Aurora-A HTRF assay begins with Aurora-A in the presence of ATPphosphorylating the biotinylated peptide PLK. The reaction incubates forabout 120 min. Detection reagents are added to quench the reaction.These agents stop the reaction by diluting out the enzyme and chelatingthe metals due to the presence of EDTA. After addition, the assay isincubated overnight to allow the detection reagents to equilibrate.

The AuroraA HTRF assay comprises 1 μL of compound in 100% DMSO, 20 μL ofATP and biotinylated PLK, and 20 μL of AuroraA-TPX2 KD GST for a finalvolume of 41 μL. The final concentration of PLK is about 1 μM. The finalconcentration of ATP is about 1 μM (Km(app)=1 μM+/−0.1) and the finalconcentration of AuroraA is about 5 nM. Buffer conditions are asfollows: 60 mM HEPES pH 7.5, 25 mM NaCl, 10 mM MgCl, 2 mM DTT, 0.05%BSA.

The assay is quenched and stopped with 160 μL of detection reagent.Detection reagents are as follows: Buffer made of 50 mM Tris, pH 7.5,100 mM NaCl, 3 mM EDTA, 0.05% BSA, 0.1% Tween20. Added to this bufferprior to reading is Steptavidin allophycocyanin (SA-APC) at a final concin the assay of 0.0005 mg/mL, and europilated anti-phosphoPLK Ab(Eu-anti-PLK) at a final conc of 0.02 nM.

The assay plate is read in either a Discovery or a RubyStar. Theeu-anti-PLK is excited at 320 nm and emits at 615 nm to excite theSA-APC which in turn emits at 655 nm. The ratio of SA-APC at 655 nm(excited due to close proximity to the Eu-anti-PLK because ofphosphorylation of the peptide) to free Eu-anti-PLK at 615 nm will givesubstrate phosphorylation.

The following exemplary compounds 42-45, 48-58, 60-64, 67, 68, 70-84,87-152, 155-162, 164-214 and 216-238 exhibited an average inhibitoryactivity of less than 10 μM (IC₅₀) in the Aurora kinase A HTRF assay.The following exemplary compounds 43-45, 48-52, 54-58, 60, 61, 63-64,67, 68, 70-84, 87-90, 92-108, 110-120, 122-123, 125143, 145-152,155-156, 158-162, 164-191, 193-214, 216-229, 231-233 and 235-238exhibited an average inhibitory activity of less than 500 nM (IC₅₀) inthe Aurora kinase A HTRF assay. Many of these Examples exhibited anaverage inhibitory activity of less than 100 nM (IC₅₀) in the Aurorakinase A HTRF assay. Examples Method F, 242-244, 468 and 469 eachexhibited an average activity in the Aurora kinase A HTRF assay of lessthan or equal to 100 nM. Method E, Examples 241, 245 and 470 exhibitedan average activity in the Aurora kinase A HTRF assay of less than orequal to 1.0 uM. Selected Examples 246-460 exhibited an average activityin the Aurora kinase A HTRF assay as follows:

“+” represents an activity (IC₅₀) in the range of 2.5 uM-500 nM;“++” represents an activity (IC₅₀) in the range of 500-100 nM; and“+++” represents an activity (IC₅₀) of less than or equal to 100 nM.

AuroraB-Homogeneous Time Resolved Fluorescent (HTRF) Kinase Assay:

The AuroraB HTRF assay begins with AuroraB in the presence of ATPphosphorylating the biotinylated peptide Histone H3. The reactionincubates for about 90 min. the reaction is quentched by addition ofdetection reagents, which stop the reaction by diluting out the enzymeand chelating the metals due to the presence of EDTA. After addition,the assay is incubated for about 60 min to allow detection reagents toequilibrate.

The AuroraB HTRF assay comprises 1 μL of compound in 100% DMSO, 20 μL ofATP and biotinylated Histone H3, and 20 μL of AuroraB FL His for a finalvolume of 41 μL. The final concentration of Histone H3 is 0.1 μM. Thefinal concentration of ATP is 23 μM (Km(app)=23 μM+/−2.6) and the finalconcentration of AuroraB is 400 pM. Buffer conditions are as follows: 50mM HEPES pH 7.5, 5 mM NaCl, 0.5 mM MgCl, 0.5 mM MnCl, 2 mM DTT, 0.05%BSA.

The assay is quenched and stopped with 160 μl, of detection reagent.Detection reagents are as follows: Buffer made of 50 mM Tris, pH 7.5,100 mM NaCl, 3 mM EDTA, 0.05% BSA, 0.1% Tween20. Added to this bufferprior to reading is Steptavidin allophycocyanin (SA-APC) at a final concin the assay of 0.001 mg/mL, and europilated anti-phosphoHistoneH3 Ab(Eu-anti-His H3) at a final conc of 0.064 nM.

The assay plate is read in either a Discovery or a RubyStar. Theeu-anti-HisH3 is excited at 320 nm and emits at 615 nm to excite theSA-APC which in turn emits at 655 nm. The ratio of SA-APC at 655 nm(excited due to close proximity to the Eu-anti-H HisH3 because ofphosphorylation of the peptide) to free Eu-anti-HisH3 at 615 nm willgive substrate phosphorylation.

The following exemplary compounds 42-58, 60-65, 67-84 87-152, 155-162,164-214 and 216-238 exhibited inhibitory activity of less than 10 μM(K_(i)) in the Aurora kinase B HTRF assay. The following exemplarycompounds 42-52, 54-58, 60-61, 63-65, 67-84 87-152, 155-162, 164-214,216-236 and 238 exhibited inhibitory activity of less than 500 nM (IC₅₀)in the Aurora kinase B HTRF assay. A vast majority of these Examplesexhibited an average inhibitory activity of less than 200 nM (IC₅₀) inthe Aurora kinase B HTRF assay. Examples Method F, 242-244, 468 and 469each exhibited an average activity in the Aurora kinase B HTRF assay ofless than or equal to 100 nM. Method E, Examples 241, 245 and 470exhibited an average activity in the Aurora kinase B HTRF assay of lessthan or equal to 1.0 uM. Selected Examples 246-460 exhibited an averageactivity in the Aurora kinase B HTRF assay as follows:

“+” represents an activity (IC₅₀) in the range of 2.5 uM-500 nM;“++” represents an activity (IC₅₀) in the range of 500-100 nM; and“+++” represents an activity (IC₅₀) of less than or equal to 100 nM.

Aurora Kinase Cell-Based Assays

HeLa cell 1-Hour Phospho-Histone Assay

The purpose of this assay is to test the inhibitory effect of Auroracompounds with respect to phosphorylation of Histone H3 in the cellularcontext. HeLa cells (9×10⁴/well) are plated in black 96-well flat-bottomtissue culture plates and incubated for 40 hours prior to compoundaddition. Compounds are serially diluted in DMSO, followed by dilutioninto MEM containing 10 mM HEPES; 10 ul/well of diluted compounds areadded to cells (0.5% DMSO final). Cells are incubated for 1 hour at 37°C. in 5% CO₂. Cells are then fixed with 3.7% formaldehyde for 10minutes, washed with wash buffer (1% goat serum and 0.1% Tween 20 inPBS), then permeabilized with 0.5% Triton X in PBS for 15 minutes. Afterwashing with wash buffer, cells are incubated with primary antibody(Upstate #06-507 anti-phospho-histone (Ser 10) antibody (pHH3) for 1hour at 10 ug/ml. After 2 washes with wash buffer, cells are incubatedwith secondary antibody (Molecular Probes #A11034 goat anti-rabbitAlexa-488 for 1 hour at 1 ug/ml+Hoechst 33342 nuclear dye at 1 ug/ml(Molecular Probes). Cells are washed 2 times with wash buffer, andbuffer replaced with PBS. Plates are scanned on the Cellomics Array Scan(6 fields, ˜2000 cells/well) and % of cells that are pHH3 positive werecalculated using the Cellomics algorithm. The following exemplarycompounds 42-45, 48-52, 54-58, 60-65, 67-76, 78-84, 87-108, 111-120,122, 123, 125-137, 140-143, 145-148, 150-156, 158-162, 164-168, 170-214,216-233 and 235-238 exhibited inhibitory activity of less than 10 μM(EC₅₀) in the phospho-histone H3 assay. The following exemplarycompounds 42-45, 49-52, 54-58, 60-61, 63-64, 67-68, 70-76, 78-84, 87-88,90, 92, 94-101, 105, 107, 108, 111-117, 119, 120, 122, 123, 125-128,130-132, 134-137, 140-143, 147-148, 150-151, 153-156, 158-159, 161-162,164-168, 170-171, 173-176, 178-188, 190-191, 193-214, 216-228, 232-233,235-236 and 238 exhibited inhibitory activity of less than 1 (EC₅₀) inthe phospho-histone H3 assay. Many of these Examples exhibitedinhibitory activity of less than 500 nM (EC₅₀) in the phospho-histone H3assay Selected Examples 246-460 exhibited an average activity in thephospho-histone H3 assay as follows:

“+” represents an activity (IC₅₀) in the range of 2.5 uM-500 nM;“++” represents an activity (IC₅₀) in the range of 500-100 nM; and“+++” represents an activity (IC₅₀) of less than or equal to 100 nM.

Indications

The compounds of the invention have Aurora kinase modulatory activity ingeneral, and inhibitory activity in particular. In one embodiment of theinvention, there is provided a method of modulating Aurora kinase enzymein a subject, the method comprising administering to the subject aneffective dosage amount of a compound of a compound of Formulas I-III.As such, the compounds of the invention may be used to treat cellularproliferation disorders, including uncontrolled cell growth and aberrantcell cycle regulation. The compounds are also useful for treatingdisorders related to hyper-proliferation of cells in normal tissue,including without limitation, non-tumor bearing and metastatic tissue.For example, one use may be to protect normal hair follicles fromchemotherapy induced alopecia.

In addition, compounds of the invention are useful for, but not limitedto, the prevention or treatment of cancer and other Aurorakinase-mediated diseases or disorders. For example, compounds of theinvention would be useful for the treatment of various solid andhematologically derived tumors, such as carcinomas, including, withoutlimitation, cancer of the bladder, breast, colon, kidney, liver, lung(including small cell lung cancer), esophagus, gall-bladder, ovary,pancreas, stomach, cervix, thyroid, prostate, and skin (includingsquamous cell carcinoma); hematopoietic tumors of lymphoid lineage(including leukemia, acute lymphocitic leukemia, acute lymphoblasticleukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma);hematopoietic tumors of myeloid lineage (including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia); tumors of mesenchymal origin (including fibrosarcoma andrhabdomyosarcoma, and other sarcomas, e.g. soft tissue and bone); tumorsof the central and peripheral nervous system (including astrocytoma,neuroblastoma, glioma and schwannomas); and other tumors (includingmelanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderomapigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi'ssarcoma).

The compounds of the invention are also useful in the treatment ofcancer related indications such as solid tumors, sarcomas (especiallyEwing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas,neuroblastoma, hematopoietic malignancies, including leukemia andlymphoma, tumor-induced pleural or pericardial effusions, and malignantascites.

The compound of the invention may also be used to treatchemotherapy-induced thrombocytopenia, since the compounds may increaseplatelet count be increasing the rate of megakaryocyte maturation.

The compounds would also be useful for treatment of ophthalmologicalconditions such as corneal graft rejection, ocular neovascularization,retinal neovascularization including neovascularization following injuryor infection, diabetic retinopathy, retrolental fibroplasia andneovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerativediseases such as gastric ulcer; pathological, but non-malignant,conditions such as hemangiomas, including infantile hemaginomas,angiofibroma of the nasopharynx and avascular necrosis of bone; anddisorders of the female reproductive system such as endometriosis. Thecompounds are also useful for the treatment of edema, and conditions ofvascular hyperpermeability.

The compounds of the invention are also useful in the treatment ofconditions wherein undesired angiogenesis, edema, or stromal depositionoccurs in viral infections such as Herpes simplex, Herpes Zoster, AIDS,Kaposi's sarcoma, protozoan infections and toxoplasmosis, followingtrauma, radiation, stroke, endometriosis, ovarian hyperstimulationsyndrome, systemic lupus, sarcoidosis, synovitis, Crohn's disease,sickle cell anemia, Lyme disease, pemphigoid, Paget's disease,hyperviscosity syndrome, Osler-Weber-Rendu disease, chronicinflammation, chronic occlusive pulmonary disease, asthma, andinflammatory rheumatoid or rheumatic disease. The compounds are alsouseful in the reduction of sub-cutaneous fat and for the treatment ofobesity.

The compounds of the invention are also useful in the treatment ofocular conditions such as ocular and macular edema, ocular neovasculardisease, scleritis, radial keratotomy, uveitis, vitritis, myopia, opticpits, chronic retinal detachment, post-laser complications, glaucoma,conjunctivitis, Stargardt's disease and Eales disease in addition toretinopathy and macular degeneration.

The compounds of the invention are also useful in the treatment ofcardiovascular conditions such as atherosclerosis, restenosis,arteriosclerosis, vascular occlusion and carotid obstructive disease.

Based on the ability to modulate kinases impacting angiogenesis, thecompounds of the invention are also useful in treatment and therapy ofproliferative diseases. Particularly, these compounds can be used forthe treatment of an inflammatory rheumatoid or rheumatic disease,especially of manifestations at the locomotor apparatus, such as variousinflammatory rheumatoid diseases, especially chronic polyarthritisincluding rheumatoid arthritis, juvenile arthritis or psoriasisarthropathy; paraneoplastic syndrome or tumor-induced inflammatorydiseases, turbid effusions, collagenosis, such as systemic Lupuserythematosus, poly-myositis, dermato-myositis, systemic sclerodermia ormixed collagenosis; postinfectious arthritis (where no living pathogenicorganism can be found at or in the affected part of the body),seronegative spondylarthritis, such as spondylitis ankylosans;vasculitis, sarcoidosis, or arthrosis; or further any combinationsthereof.

The compounds of the invention can also be used as active agents againstsuch disease states as arthritis, atherosclerosis, psoriasis,hemangiomas, myocardial angiogenesis, coronary and cerebral collaterals,ischemic limb angiogenesis, wound healing, peptic ulcer Helicobacterrelated diseases, fractures, cat scratch fever, rubeosis, neovascularglaucoma and retinopathies such as those associated with diabeticretinopathy or macular degeneration. In addition, some of thesecompounds can be used as active agents against solid tumors, malignantascites, hematopoietic cancers and hyperproliferative disorders such asthyroid hyperplasia (especially Grave's disease), and cysts (such ashypervascularity of ovarian stroma, characteristic of polycystic ovariansyndrome (Stein-Leventhal syndrome)) since such diseases require aproliferation of blood vessel cells for growth and/or metastasis.

The compounds of the invention can also be used as active agents againstburns, chronic lung disease, stroke, polyps, anaphylaxis, chronic andallergic inflammation, ovarian hyperstimulation syndrome, braintumor-associated cerebral edema, high-altitude, trauma or hypoxiainduced cerebral or pulmonary edema, ocular and macular edema, ascites,and other diseases where vascular hyperpermeability, effusions,exudates, protein extravasation, or edema is a manifestation of thedisease. The compounds will also be useful in treating disorders inwhich protein extravasation leads to the deposition of fibrin andextracellular matrix, promoting stromal proliferation (e.g. fibrosis,cirrhosis and carpal tunnel syndrome).

Besides being useful for human treatment, these compounds are useful forveterinary treatment of companion animals, exotic animals and farmanimals, including mammals, rodents, and the like. For example, animalsincluding horses, dogs, and cats may be treated with compounds providedby the invention.

Formulations

Also embraced within this invention is a class of pharmaceuticalcompositions, also referred to as medicaments, comprising the activecompounds of Formulas I-III in association with one or more non-toxic,pharmaceutically-acceptable carriers and/or diluents and/or adjuvants(collectively referred to herein as “carrier” materials) and, ifdesired, other active ingredients. The pharmaceutically active compoundsof this invention can be processed in accordance with conventionalmethods of pharmacy to produce medicinal agents for administration topatients, including humans and other mammals.

The compounds of the present invention may be administered to a subjectby any suitable route, preferably in the form of a pharmaceuticalcomposition, adapted to such a route, and in a dose effective for thetreatment intended. The compounds and compositions of the presentinvention may, for example, be administered orally, mucosally,topically, rectally, pulmonarily such as by inhalation spray, orparentally including intravascularly, intravenously, intraperitoneally,subcutaneously, intramuscularly intrasternally and infusion techniques,in dosage unit formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants, and vehicles.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of active ingredient from about 1 to 2000 mg, andtypically from about 1 to 500 mg. A suitable daily dose for a human orother mammal may vary widely depending on the condition of the patientand other factors, but, once again, can be determined using routinemethods and practices.

The amount of compounds which are administered and the dosage regimenfor treating a disease condition with the compounds and/or compositionsof this invention depends on a variety of factors, including the age,weight, sex and medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.01 to 500 mg/kg, advantageously between about 0.01 andabout 50 mg/kg, and more advantageously about 0.01 and about 30 mg/kgbody weight may be appropriate. The daily dose can be administered inone to four doses per day.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants or “excipients”appropriate to the indicated route of administration. If administered ona per dose basis, the compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, cellulose alkylesters, talc, stearic acid, magnesium stearate, magnesium oxide, sodiumand calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, to formthe final formulation. For example, the active compound(s) andexcipient(s) may be tableted or encapsulated by known and acceptedmethods for convenient administration. Examples of suitable formulationsinclude, without limitation, pills, tablets, soft and hard-shell gelcapsules, troches, orally-dissolvable forms and delayed orcontrolled-release formulations thereof. Particularly, capsule or tabletformulations may contain one or more controlled-release agents, such ashydroxypropylmethyl cellulose, as a dispersion with the activecompound(s).

In the case of psoriasis and other skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, pastes, suspensions andthe like) and drops suitable for administration to the eye, ear, ornose. A suitable topical dose of active ingredient of a compound of theinvention is 0.1 mg to 150 mg administered one to four, preferably oneor two times daily. For topical administration, the active ingredientmay comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight ofthe formulation, although it may comprise as much as 10% w/w, butpreferably not more than 5% w/w, and more preferably from 0.1% to 1% ofthe formulation.

When formulated in an ointment, the active ingredients may be employedwith either paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base. If desired, the aqueous phase of the cream base may include,for example at least 30% w/w of a polyhydric alcohol such as propyleneglycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethyleneglycol and mixtures thereof. The topical formulation may desirablyinclude a compound, which enhances absorption or penetration of theactive ingredient through the skin or other affected areas. Examples ofsuch dermal penetration enhancers include DMSO and related analogs.

The compounds of this invention can also be administered by transdermaldevice. Preferably transdermal administration will be accomplished usinga patch either of the reservoir and porous membrane type or of a solidmatrix variety. In either case, the active agent is deliveredcontinuously from the reservoir or microcapsules through a membrane intothe active agent permeable adhesive, which is in contact with the skinor mucosa of the recipient. If the active agent is absorbed through theskin, a controlled and predetermined flow of the active agent isadministered to the recipient. In the case of microcapsules, theencapsulating agent may also function as the membrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase, which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include, for example, Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodiumlauryl sulfate, glyceryl distearate alone or with a wax, or othermaterials well known in the art.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. The active ingredients are preferably present in suchformulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%and particularly about 1.5% w/w.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie.propylene glycol) or micellar solubilization (ie. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

Combinations

While the compounds of the invention can be dosed or administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or in conjunction with otheragents. When administered as a combination, the therapeutic agents canbe formulated as separate compositions that are administeredsimultaneously or sequentially at different times, or the therapeuticagents can be given as a single composition.

The phrase “co-therapy” (or “combination-therapy”), in defining use of acompound of the present invention and another pharmaceutical agent, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as in a singlecapsule having a fixed ratio of these active agents or in multiple,separate capsules for each agent.

Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of cancer, such as withradiation therapy or with neoplastic or cytotoxic agents.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof Formulas I-III may also be administered sequentially with knownanticancer or cytotoxic agents when a combination formulation isinappropriate. The invention is not limited in the sequence ofadministration; compounds of the invention may be administered eitherprior to, simultaneous with or after administration of the knownanticancer or cytotoxic agent.

There are large numbers of antineoplastic agents available in commercialuse, in clinical evaluation and in pre-clinical development, which wouldbe selected for treatment of neoplasia by combination drug chemotherapy.Such antineoplastic agents fall into several major categories, namely,antibiotic-type agents, alkylating agents, antimetabolite agents,hormonal agents, immunological agents, interferon-type agents and acategory of miscellaneous agents.

Alternatively, the compounds of the invention may also be used inco-therapies with other anti-neoplastic agents, such as other kinaseinhibitors including angiogenic agents such as VEGFR inhibitors, p38inhibitors and CDK inhibitors, TNF inhibitors, metallomatrix proteasesinhibitors (MMP), COX-2 inhibitors including celecoxib, rofecoxib,parecoxib, valdecoxib, and etoricoxib, NSAID's, SOD mimics or α_(v)β₃inhibitors.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes, which are obvious to one skilled in the art, are intendedto be within the scope and nature of the invention, which are defined inthe appended claims. All mentioned references, patents, applications andpublications, are hereby incorporated by reference in their entirety, asif here written.

1. A compound of Formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, whereineach of A¹ and A², independently, is N or CR⁹, provided that at leastone of A¹ and A² is N; C¹ is N or CR¹⁰; C² is N or CH; D is

wherein D¹ is N or CR¹¹; D² is N or CR¹²; D³ is N or CR²; D⁴ is NR^(1a),O, S or CR¹²; D⁵ is N or CR²; R¹ is H, OR¹⁴, SR¹⁴, OR¹⁵, SR¹⁵, NR¹⁴R¹⁵,NR¹⁵R¹⁵, (CHR¹⁵)_(n)R¹⁴, (CHR¹⁵)_(n)R¹⁵ or R¹⁵, wherein n is 0, 1, 2, 3or 4; R^(1a) is H, CN or C₁₋₁₀alkyl; alternatively R¹ taken togetherwith either of R¹¹ and R^(1a) and the carbon or nitrogen atoms to whichthey are attached form a partially or fully unsaturated 5- or 6-memberedring of carbon atoms optionally including 1-3 heteroatoms selected fromO, N and S, and the ring optionally substituted independently with 1-3substituents of oxo, R¹⁵, SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, OC(O)R¹⁵, COOR¹⁵,C(O)R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁴R¹⁵ or NR¹⁵R¹⁵; and R² is SR¹⁴, OR¹⁴, SR¹⁵,OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵,C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴,S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵ or R¹⁵; L¹ is NR³, O, S,C(O), S(O), SO₂ or CR³R³; L² is NR³, O, S, C(O), S(O), SO₂ or CR³R³; Zis a fully unsaturated 5-6 membered first monocyclic ring, said firstring (1) formed of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, (2) optionally fused to a partially or fullysaturated or fully unsaturated 5-6 membered second monocyclic ringformed of carbon atoms optionally including 1-3 heteroatoms selectedfrom O, N, or S, and (3) wherein 0, 1, 2 or 3 atoms of each of saidfirst and second ring is optionally substituted independently with 1-5substituents of R⁵; each of R³ and R⁴, independently, is SR¹⁴, OR¹⁴,SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵,C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵,NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR^(15c)(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵),OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵,NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵ or R¹⁵; alternatively, eitherof R³ or R⁴, independently, taken together with R¹⁰ and the carbon atomsto which they are attached form a partially or fully unsaturated 5- or6-membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and the ring optionally substitutedindependently with 1-3 substituents of R¹³, R¹⁴ or R¹⁵; each R⁵,independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴,C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵; each of R⁶, R⁷ and R⁸, independently, is R¹³, R¹⁴ or R¹⁵;alternatively, either of R⁶ or R⁸, independently, taken together with R⁷and the carbon atoms to which they are attached form a fully saturatedor partially or fully unsaturated 5- or 6-membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, and thering optionally substituted independently with 1-4 substituents of R¹³,R¹⁴ or R¹⁵; each of R⁹, R¹⁰, R¹¹ and R¹², independently, is SR¹⁴, OR¹⁴,SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵,C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵,NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵),OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵,NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵ or R¹⁵; R¹³ is SR¹⁴, OR¹⁴,SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, OC(O)R¹⁴, OC(O)R¹⁵,COOR¹⁴, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵,C(O)C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵,NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵ or NR¹⁵S(O)₂NR¹⁵R¹⁵; R¹⁴ is a partiallyor fully saturated or fully unsaturated 5-8 membered monocyclic, 6-12membered bicyclic, or 7-14 membered tricyclic ring system, the ringsystem formed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, the heteroatoms selected from O, N, or S, wherein 0, 1, 2 or3 atoms of each ring is optionally substituted independently with 1-5substituents of R¹⁵; and R¹⁵ is H, halo, haloalkyl, haloalkoxyl, oxo,CN, OH, SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated orpartially or fully unsaturated 5-8 membered monocyclic, 6-12 memberedbicyclic, or 7-14 membered tricyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein each ofthe C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamine, dimethylamine, ethylamine, diethylamine, propylamine,isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl;provided that (1) no more than one of D¹, D² and D³ is N, and (2) eachof L¹ and L² is, independently, bound to the first ring of Z.
 2. Thecompound of claim 1, or a stereoisomer or pharmaceutically acceptablesalt thereof, wherein D is

wherein D¹ is N, D² is CR¹² and D³ is CH.
 3. The compound of claim 1, ora stereoisomer or pharmaceutically acceptable salt thereof, wherein D is

wherein D¹ is CR¹¹, D² is N and D³ is CH.
 4. The compound of claim 1, ora stereoisomer or pharmaceutically acceptable salt thereof, wherein C¹is CR¹⁰ and R¹⁰ is H, halo, haloalkyl, haloalkoxyl, CN, OH, SH, NO₂,NH₂, acetyl, C₁₋₁₀-alkyl or C₁₋₁₀-alkoxyl; C² is N; and R² is H, halo,NO₂, CN, C₁₋₁₀alkyl or C₁₋₁₀alkoxyl.
 5. The compound of claim 1, or astereoisomer or pharmaceutically acceptable salt thereof, wherein L¹ isNR¹⁵, O, CHR¹⁵, S, C(O), S(O) or SO₂; and R² is H, halo, NO₂, CN,C₁₋₁₀alkyl or C₁₋₁₀alkoxyl.
 6. The compound of claim 5, or astereoisomer or pharmaceutically acceptable salt thereof, wherein L² isNR¹⁵, O or S; each of R³, R⁴ and R⁹, independently, is H; C¹ is CR¹⁰;and Z is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl,imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, oxazolyl,oxadiazolyl, isoxazolyl or isothiazolyl, wherein L¹ and L², together,are para-oriented to one another on ring Z, wherein ring Z is optionallysubstituted with 1-5 substitutions of R¹⁵.
 7. The compound of claim 6,or a stereoisomer or pharmaceutically acceptable salt thereof, whereinR⁷ and R⁸ taken together with the carbon atoms to which they areattached form a fully saturated or partially or fully unsaturated 5- or6-membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and the ring optionally substitutedindependently with 1-4 substituents of R¹³, R¹⁴ or R¹⁵.
 8. The compoundof claim 6, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein each of A¹ and A², independently, is N; and R⁶ isphenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyazinyl,triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl,phthalazinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl,thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl,benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl, cycloheptyl or pyranyl,each of which is optionally substituted independently with 1-5substituents of R¹⁵.
 9. The compound of claim 1, or a stereoisomer orpharmaceutically acceptable salt thereof, wherein D is


10. The compound of claim 1 having a Formula II:

or a stereoisomer or pharmaceutically acceptable salt thereof, whereineach of A¹ and A², independently, is N or CR⁹, provided that at leastone of A¹ and A² is N; each of B¹, B², B³ and B⁴, independently, is N orCR⁵, provided that no more than two of B¹, B², B³ and B⁴ is N; C¹ is Nor CR¹⁰; D¹ is N or CR¹¹; D² is N or CR¹²; L¹ is NR³, O, S or CR³R³; L²is NR³, O, S or CR³R³; R¹ is OR¹⁴, SR¹⁴, OR¹⁵, SR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,(CHR¹⁵)_(n)R¹⁴, (CHR¹⁵)_(n)R¹⁵ or R¹⁵; alternatively R¹ and R¹¹ takentogether with the carbon atoms to which they are attached form apartially or fully unsaturated 5- or 6-membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N and S, and thering optionally substituted independently with 1-3 substituents of oxo,R¹⁵, SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴R¹⁵ or NR¹⁵R¹⁵; R² is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵,NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵ or R¹⁵; each of R³ and R⁴, independently, isSR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵ or R¹⁵;alternatively, either of R³ or R⁴, independently, taken together withR¹⁰ and the carbon atoms to which they are attached form a partially orfully unsaturated 5- or 6-membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-3 substituents of R¹³, R¹⁴or R¹⁵; each R⁵ is, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵,NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵; R⁶ is R¹³ or R¹⁴; each of R⁷ and R⁸, independently, is R¹³, R¹⁴or R¹⁵; alternatively, either of R⁷ and R⁸ taken together with thecarbon atoms to which they are attached form a fully saturated orpartially or fully unsaturated 5- or 6-membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, and thering optionally substituted independently with 1-4 substituents of R¹³,R¹⁴ or R¹⁵; each of R⁹, R¹⁰, R¹¹ and R¹², independently, is SR¹⁴, OR¹⁴,SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵ or R¹⁵; R¹³ is SR¹⁴,OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, OC(O)R¹⁴,OC(O)R¹⁵, COOR¹⁴, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴,NR¹⁵C(O)R¹⁵, C(O)C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), NR¹⁵C(O)C(O)NR¹⁴R¹⁵,NR¹⁵C(O)C(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵,NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵ or NR¹⁵S(O)₂NR¹⁵R¹⁵; R¹⁴ isa partially or fully saturated or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, the ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, the heteroatoms selected from O, N, or S,wherein 0, 1, 2 or 3 atoms of each ring is optionally substitutedindependently with 1-5 substituents of R¹⁵; R¹⁵ is H, halo, haloalkyl,haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; and n is 0, 1, 2, 3 or 4; providedthat no more than one of D¹ and D² is N.
 11. The compound of claim 10,or a stereoisomer or pharmaceutically acceptable salt thereof, whereineach of A¹ and A², independently, is N; each of B¹, B², B³ and B⁴,independently, is N or CR⁵, provided that no more than one of B¹, B², B³and B⁴ is N; C¹ is CR¹⁰; D¹ is N or CR¹¹; D² is N or CR¹²; L¹ is NH, Oor S; L² is NH, O or S; provided that both of L¹ and L² are not either Oor S; R¹ is H, halo, haloalkyl, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, NHR¹⁴, NHR¹⁵,OR¹⁵, SR¹⁵ or CH₂R¹⁵; R² is H, halo, NO₂, CN, C₁₋₁₀alkyl orC₁₋₁₀alkoxyl; each of R³ and R⁴, independently, is SR¹⁵, OR¹⁵, NR¹⁴R¹⁵,NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵ or R¹⁵; each R⁵ is, independently, is SR¹⁵,OR¹⁵, NR¹⁵R¹⁵, C(O)R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵(COOR¹⁵), S(O)₂R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁵,NR¹⁵C(O)C(O)NR¹⁴R¹⁵ or R¹⁵; R⁶ is R¹⁴; each of R⁷ and R⁸, independently,is R¹⁵; alternatively, either of R⁷ and R⁸ taken together with thecarbon atoms to which they are attached form a partially or fullyunsaturated 5- or 6-membered ring of carbon atoms optionally including1-3 heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-4 substituents of R¹³ or R¹⁵; and eachof R⁹, R¹⁰, R¹¹ and R¹², independently, is R¹⁵.
 12. The compound ofclaim 10 or a stereoisomer or pharmaceutically acceptable salt thereof,wherein, R¹ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, (CHR¹⁵)_(n)R¹⁴, (CHR¹⁵)_(n)R¹⁵ or R¹⁵;alternatively R¹ and R¹¹ taken together with the carbon atoms to whichthey are attached form a partially or fully unsaturated 5- or 6-memberedring of carbon atoms optionally including 1-3 heteroatoms selected fromO, N and S, and the ring optionally substituted independently with 1-3substituents of R¹⁵; R² is H, halo, haloalkyl, CN, NO₂, NH₂, OH, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; each of R³ and R⁴, independently, isH, halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamine, dimethylamine, ethylamine, diethylamine, propylamine,isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl; eachR⁵ is, independently, is H, halo, haloalkyl, CN, NO₂, NH₂, OH, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine ordiisopropylamine; R⁶ is R¹³ or R¹⁴; each of R⁷ and R⁸, independently, isR¹⁵; alternatively, either of R⁷ and R⁸ taken together with the carbonatoms to which they are attached form a partially or fully unsaturated5- or 6-membered ring of carbon atoms optionally including 1-3heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-4 substituents of R¹³, R¹⁴ or R¹⁵; andeach of R⁹, R¹⁰, R¹¹ and R¹², independently, is H, halo, haloalkyl, CN,NO₂, NH₂, OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamine,dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine,dipropylamine or diisopropylamine.
 13. The compound of claim 10 or astereoisomer or pharmaceutically acceptable salt thereof, wherein, eachof A¹ and A², independently, is N; and R⁷ and R⁸ taken together with thecarbon atoms to which they are attached form a fully unsaturated 5- or6-membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and the ring optionally substitutedindependently with 1-4 substituents of R¹³, R¹⁴ or R¹⁵.
 14. The compoundof claim 13 or a stereoisomer or pharmaceutically acceptable saltthereof, wherein R⁶ is phenyl, naphthyl, pyridyl, pyrimidinyl,pyridazinyl, pyazinyl, triazinyl, quinolinyl, dihydroquinolinyl,tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,quinazolinyl, isoquinazolinyl, phthalazinyl, thiophenyl, furyl,tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl,triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, benzothiazolyl,oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, isoxazolyl,isothiazolyl, indolyl, azaindolyl, 2,3-dihydroindolyl, isoindolyl,indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,imidazo-pyridinyl, purinyl, benzotriazolyl, oxazolinyl, isoxazolinyl,thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl, dioxozinyl, 2,3-dihydro-1,4-benzoxazinyl,1,3-benzodioxolyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl,cyclohexyl, cycloheptyl or pyranyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹⁵.
 15. The compoundof claim 10, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein, C¹ is CH; D¹ is N; D² is CR¹² wherein R¹² is H, halo,NO₂, CN, C₁₋₁₀alkyl or C₁₋₁₀alkoxyl; L¹ is NH, O or S; L² is NH; R¹ isH, halo, haloalkyl, acetyl, C₁₋₁₀-alkyl or NHR¹⁵; each of R², R³ and R⁴,independently, is H, halo, C₁₋₁₀alkyl or C₁₋₁₀alkoxyl; R⁶ is R¹⁴; and R⁷and R⁸ taken together with the carbon atoms to which they are attachedform a partially or fully unsaturated 5- or 6-membered ring of carbonatoms optionally including 1-3 heteroatoms selected from O, N, or S, andthe ring optionally substituted independently with 1-4 substituents ofR¹³ or R¹⁵.
 16. A compound of Formula III:

or a stereoisomer or pharmaceutically acceptable salt thereof, whereineach of A¹ and A², independently, is N or CR⁹, provided that at leastone of A¹ and A² is N; each of B¹, B², B³ and B⁴, independently, is N orCR⁵, provided that no more than two of B¹, B², B³ and B⁴ is N; C¹ is Nor CR¹⁰; L¹ is O, S, C(O), S(O), SO₂ or CR³R³; L² is NR³, O, S or CR³R³;R¹ is OR¹⁴, SR¹⁴, OR¹⁵, SR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, (CHR¹⁵)_(n)R¹⁴,(CHR¹⁵)_(n)R¹⁵ or R¹⁵; alternatively R¹ and R¹¹ taken together with thecarbon atoms to which they are attached form a partially or fullyunsaturated 5- or 6-membered ring of carbon atoms optionally including1-3 heteroatoms selected from O, N and S, and the ring optionallysubstituted independently with 1-3 substituents of R¹⁵, SR¹⁴, OR¹⁴,SR¹⁵, OR¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁴R¹⁵ or NR¹⁵R¹⁵;R² is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵,COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴,NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵C(O)C(O)R¹⁵,NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵,S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵ or R¹⁵; each of R³ and R⁴, independently, is SR¹⁴, OR¹⁴,SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵ or R¹⁵; alternatively,either of R³ or R⁴, independently, taken together with R¹⁰ and thecarbon atoms to which they are attached form a partially or fullyunsaturated 5- or 6-membered ring of carbon atoms optionally including1-3 heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-3 substituents of R¹³, R¹⁴ or R¹⁵; eachR⁵ is, independently, is SR¹⁴, OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵,C(O)R¹⁴, C(O)R¹⁵, COOR¹⁵, OC(O)R¹⁵, C(O)C(O)R¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁵), OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁵S(O)₂R¹⁴,NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁴R¹⁵, NR¹⁵C(O)C(O)NR¹⁵R¹⁵or R¹⁵; R⁶ is R¹³ or R¹⁴; each of R⁷ and R⁸, independently, is R¹³, R¹⁴or R¹⁵; alternatively, either of R⁷ and R⁸ taken together with thecarbon atoms to which they are attached form a fully saturated orpartially or fully unsaturated 5- or 6-membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, and thering optionally substituted independently with 1-4 substituents of R¹³,R¹⁴ or R¹⁵; each of R⁹, R¹⁰, R¹¹ and R¹², independently, is SR¹⁴, OR¹⁴,SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵ or R¹⁵; R¹³ is SR¹⁴,OR¹⁴, SR¹⁵, OR¹⁵, NR¹⁴R¹⁵, NR¹⁵R¹⁵, C(O)R¹⁴, C(O)R¹⁵, OC(O)R¹⁴,OC(O)R¹⁵, COOR¹⁴, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁵C(O)R¹⁴,NR¹⁵C(O)R¹⁵, C(O)C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵,NR¹⁵C(O)C(O)R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), NR¹⁵C(O)C(O)NR¹⁴R¹⁵,NR¹⁵C(O)C(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵,NR¹⁵S(O)₂R¹⁴, NR¹⁵S(O)₂R¹⁵, NR¹⁵S(O)₂NR¹⁴R¹⁵ or NR¹⁵S(O)₂NR¹⁵R¹⁵; R¹⁴ isa partially or fully saturated or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, the ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, the heteroatoms selected from O, N, or S,wherein 0, 1, 2 or 3 atoms of each ring is optionally substitutedindependently with 1-3 substituents of R¹⁵; R¹⁵ is H, halo, haloalkyl,haloalkoxyl, oxo, CN, OH, SH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; and n is 0, 1, 2, 3 or
 4. 17. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,selected from:′2-(4-(4-((4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)amino)-1-phthalazinyl)phenyl)ethanol;′N-(5-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-2-pyridinyl)-4-phenyl-1-phthalazinamine;′N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenylfuro[2,3-d]pyridazin-7-amine;′4-phenyl-N-(4-((2-(4-pyridinyl)phenyl)oxy)phenyl)-1-phthalazinamine;′N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(2,6-bis(methyloxy)phenyl)-1-phthalazinamine;′(1R)-1-(4-(4-((4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)amino)-1-phthalazinyl)phenyl)ethanol;′N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4,5-dimethyl-6-(4-methyl-2-thienyl)-3-pyridazinamine;′N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenyl-1-isoquinolinamine;′N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-isoquinolinamine;′4-phenyl-N-(6-((3-(2-((3-(1-piperidinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)-3-pyridinyl)-1-phthalazinamine;′N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-cyclohexyl-1-phthalazinamine;′N-(4-((3-(2-((3-(4-methyl-1-piperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(6-methyl-2-pyridinyl)-1-phthalazinamine;′4-(6-methyl-2-pyridinyl)-N-(4-((3-(2-((3-(1-piperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-1-phthalazinamine;′N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(3-fluoro-1-piperidinyl)-1-phthalazinamine;′4-(2-((4-((4-phenyl-1-phthalazinyl)amino)phenyl)oxy)-3-pyridinyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one;′4-(4-methyl-1,3-thiazol-2-yl)-N-(4-((3-(5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)-2-pyridinyl)oxy)phenyl)-1-phthalazinamine;′N-(4-((3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-pyridinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine;′N-(6-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)-3-pyridinyl)-4-(5-methyl-2-pyridinyl)-1-phthalazinamine;′N-(4-((3-(5-fluoro-2-((3-(4-methyl-1-piperazinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine;′N-(4-((3-(3-amino-1H-pyrazol-4-yl)-2-pyridinyl)oxy)phenyl)-4-(4-methylphenyl)-1-phthalazinamine;′N-(4-((3-(3-amino-1H-pyrazol-4-yl)-2-pyridinyl)oxy)phenyl)-4-(phenylmethyl)-1-phthalazinamine;′N-(4-((3-(3-amino-1H-pyrazol-4-yl)-2-pyridinyl)oxy)phenyl)-4-phenylthieno[2,3-d]pyridazin-7-amine;′N-(4-((3-(3-amino-1H-pyrazol-4-yl)-2-pyridinyl)oxy)-3-fluorophenyl)-4-phenyl-1-phthalazinamine;′N-(6-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)-3-pyridinyl)-4-(3-(methylsulfonyl)phenyl)-1-phthalazinamine;′N-(4-((3-(2-((3-((2S,5S)-2,5-dimethyl-4-morpholinyl)propyl)amino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine;′N-(6-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)-3-pyridinyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine;′1-(4-((4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)amino)-1-phthalazinyl)-3-piperidinol;′2-(4-((6-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)-3-pyridinyl)amino)-1-phthalazinyl)phenol;′2-(4-((6-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)-3-pyridinyl)amino)-1-phthalazinyl)phenyldihydrogen phosphate;′2-((4-((4-(4-methyl-2-thienyl)-1-phthalazinyl)amino)phenyl)oxy)-3,4′-bipyridin-2′-amine;′2-((4-((4-ethyl-6-phenyl-3-pyridazinyl)amino)phenyl)oxy)-3,4′-bipyridin-2′-amine;′2-((4-((4-methyl-6-(4-methyl-1,3-thiazol-2-yl)-3-pyridazinyl)amino)phenyl)oxy)-3,4′-bipyridin-2′-amine;′2-((4-((4-(2-(methyloxy)phenyl)-1-phthalazinyl)amino)phenyl)oxy)-3,4′-bipyridin-2′-amine;′N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-6-phenyl-4-propyl-3-pyridazinamine;and′N-(4-((2-(methyloxy)-6-(4-pyridinyl)phenyl)oxy)phenyl)-4-phenyl-1-phthalazinamine.18. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a dose effective amount of the compound of any ofclaim
 10. 19. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a dose effective amount of a compound of claim17.
 20. A method of treating cancer in a subject, the method comprisingadministering to the subject a dose effective amount of a compound ofclaim
 10. 21. A method of treating breast cancer, colon cancer, kidneycancer, liver cancer, lung small cell lung cancer, esophagus cancer,gall-bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer,cervical cancer, thyroid cancer, prostate cancer and skin cancer in asubject, the method comprising administering to the subject a doseeffective amount of a compound of claim
 10. 22. A method of treatingbreast cancer, colon cancer, kidney cancer, liver cancer, lung smallcell lung cancer, esophagus cancer, gall-bladder cancer, ovarian cancer,pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer,prostate cancer and skin cancer in a subject, the method comprisingadministering to the subject a dose effective amount of a compoundselected fromN-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(3-methyl-5-isothiazolyl)-1-phthalazinamine,N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(6-methyl-2-pyridinyl)-1-phthalazinamine,N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine,N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(5-methyl-2-pyridinyl)-1-phthalazinamineandN-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(3-methyl-1H-pyrazol-1-yl)-1-phthalazinamine,or a pharmaceutically acceptable salt thereof.
 23. A method of treatinga cell proliferation disorder selected from (a) a solid orhematologically derived tumor selected from cancer of the bladder,breast, colon, kidney, liver, lung small cell lung cancer, esophagus,gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate andskin, (b) a hematopoietic tumor of lymphoid lineage selected fromleukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia,B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin'slymphoma, hairy cell lymphoma and Burkett's lymphoma, (c) ahematopoietic tumor of myeloid lineage selected from acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia (d) a tumor of mesenchymal origin selected from fibrosarcomaand rhabdomyosarcoma, (e) a tumor of the central and peripheral nervoussystem selected from astrocytoma, neuroblastoma, glioma and schwannoma,and (f) a melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderomapigmentosum, keratoctanthoma, thyroid follicular cancer or Kaposi'ssarcoma or a combination thereof in a subject, the method comprisingadministering to the subject a dose effective amount of a compound ofclaim
 10. 24. A method of making a compound of claim 1, the methodcomprising the step of reacting compound of Formula A

with a compound of Formula B

wherein C¹, C², D, L¹, Z and R³⁻⁴ of compound of formula A and A¹, A²and R⁶⁻⁸ of compound of formula B are as defined in claim 1, and X is ahalogen, to make a compound of Formula I.